transforming-growth-factor-beta and Hypertension--Renal

In patients with progressive podocyte diseases, such as focal segmental glomerulosclerosis and membranous nephropathy, there is enhanced expression of transforming growth factor (TGF-β) in podocytes. Biomechanical strain in these diseases may cause overexpression of TGF-β and angiotensin II (Ang II) by podocytes. Oxidative stress induced by Ang II may activate the latent TGF-β. Increased TGF-β activity by podocytes may induce not only the thickening of the glomerular basement membrane (GBM), but also podocyte apoptosis and/or detachment from the GBM, initiating the development of glomerulosclerosis. Furthermore, mesangial matrix expansion frequently occurs in podocyte diseases in association with the development of glomerulosclerosis. This review examines open questions on the pathogenic role of TGF-β that links podocyte injury to GBM thickening, podocyte loss, mesangial matrix expansion and glomerulosclerosis in podocyte diseases. It also describes paracrine regulatory mechanisms of podocyte TGF-β on mesangial cells leading to increased matrix synthesis.

Topics: Angiotensin II; Animals; Biomechanical Phenomena; Connective Tissue Growth Factor; Denys-Drash Syndrome; Diabetic Nephropathies; Glomerular Basement Membrane; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Humans; Hypertension, Renal; Kidney Diseases; Models, Biological; Paracrine Communication; Podocytes; Signal Transduction; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Topics: Animals; Combined Modality Therapy; Diabetic Nephropathies; Disease Progression; Glycation End Products, Advanced; Humans; Hyperglycemia; Hypertension, Renal; Kidney Glomerulus; Peptidyl-Dipeptidase A; Polymers; Protein Kinase C; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Transforming Growth Factor beta

Topics: Angiotensin II; Animals; Humans; Hypertension, Renal; Nephrosclerosis; Transforming Growth Factor beta

A large body of data has now implicated elevations in the cytokine transforming growth factor-beta (TGF-beta) as a key mediator of tissue fibrosis. A number of mechanisms by which TGF-beta can be increased have been identified. Among them is the potent vasoconstrictor angiotensin II (ANG II). In vitro data indicate that ANG II, independent of blood pressure, increases synthesis and decreases degradation of pathological extracellular matrix components. These effects are largely, but not completely, mediated by ANG II induction of TGF-beta. In many models of renal fibrosis and in a number of human renal diseases, blockade of ANG II retards disease progression. Very recent studies indicate that ANG II blockade suppresses TGF-beta, whether the therapeutic agent is an angiotensin converting enzyme inhibitor or an ANG II type 1 receptor antagonist. These data suggest that an important antifibrotic, therapeutic effect of ANG II blockade is reduction of TGF-beta overexpression and raise the question of whether disease progression could be further retarded if ANG II blockade were optimized for maximal TGF-beta reduction rather than for normalization of systemic blood pressure.

Topics: Angiotensin II; Animals; Disease Models, Animal; Fibrosis; Humans; Hypertension, Renal; Kidney Diseases; Transforming Growth Factor beta

To verify the benefit of renin-angiotensin system blockade in hypertension, the effects of 24 weeks' losartan and ramipril treatment, both alone and in combination, on urinary albumin excretion (UAE) and circulating transforming growth factor beta1 (TGF beta1) have been evaluated in hypertensive subjects with minor renal abnormalities.. Fifty-one patients with stage 1 and 2 essential hypertension and with UAE > or = 20 mg/24 h but with maintained renal function have been included. After a 4-week run-in with placebo administration, a randomized double-blind, three-arm double-dummy trial was used. All the hypertensives (HT) were allocated randomly to three treatment arms (17 patients for each group) and they were single-matched for age, gender, body mass index (BMI), systolic and diastolic blood pressure. Active treatment consisted of losartan (50 mg/day), ramipril (5 mg/day) and combined (losartan 50 mg/day plus ramipril 5 mg/day) for 24 weeks. Hydrochlorothiazide 12.5 mg/day was added in HT patients with uncontrolled blood pressure (> or = 140/90 mmHg) during the active treatment period. In all patients UAE, by immunonephelometric assay; circulating TGF beta1 by a solid-phase specific sandwich enzyme-linked immunosorbent assay (ELISA); and blood urea nitrogen (BUN), creatinine and creatinine clearance and potassium, by routine laboratory methods, were determined after placebo treatment and 24 weeks follow-up.. The three treatment groups were comparable for gender, age, BMI, blood pressure, UAE and renal function measurements. During the active treatment period it was necessary to add hydrochlorothiazide in five patients--two each of the losartan and ramipril groups and one of the combined group. At the end of treatment, significant (P < 0.05) reductions in systolic, diastolic and mean blood pressure, UAE and TGF beta1 levels were observed in all the groups. No change in renal function measurements were observed. The absolute and percentage reduction in UAE and TGF beta1 were significantly higher in the combined group than in the losartan or ramipril groups. No significant changes in absolute and percentage reduction of systolic, diastolic and mean blood pressure were found. All treatment regimens were well tolerated with few and transient side-effects.. These data indicate an additional renoprotective effect of dual blockade of the renin-angiotensin system (RAS) in hypertensive patients with minor renal abnormalities. In addition, the contemporaneus and marked decrease in TGF beta1 and UAE levels in hypertensives treated with combined therapy might indicate the presence of a subset of subjects who may benefit from complete RAS blockade.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Drug Therapy, Combination; Female; Humans; Hypertension, Renal; Kidney; Losartan; Male; Middle Aged; Ramipril; Renal Insufficiency; Severity of Illness Index; Transforming Growth Factor beta; Transforming Growth Factor beta1

Growth factors, cytokines, and the renin-angiotensin system (RAS) are involved in chronic allograft dysfunction. However, it is unclear whether clinical evaluations of TGFBeta1 and the RAS in longterm stable transplant patients can predict the development of chronic allograft dysfunction.. Urinary TGFBeta1 excretion and the response of plasma renin activity (PRA) to angiotensin I converting-enzyme inhibition (ACE-I) were prospectively examined in transplant patients who had had stable graft function (n = 16) for at least 1 year after renal transplantation. Four-year follow-up studies were undertaken to evaluate the impact of these parameters on the development of chronic allograft dysfunction.. Urinary TGFBeta1 excretion and PRA response to ACE-I in renal transplant patients who developed chronic allograft nephropathy 4 years after the evaluations (n = 7) were significantly higher and greater, respectively, than these values in those who did not ( n = 9; P < 0.01). If the cutoff level for urinary TGFBeta1 excretion was 250 pg/min, the 4-year positive predictive value (PPV) with respect to the development of chronic allograft nephropathy was 83% and the negative predictive value (NPV) was 78% (sensitivity [sen.], 71%; specificity [sp.], 88%). If the cutoff level for PRA at 60 min after ACE-I was 4.0 ng/ml per h, the 4-year PPV was 71% and NPV was 75% (sen., 70%; sp., 75%). The stable transplant patients with high TGFBeta1 excretion and exaggerated PRA response showed significantly higher rates of chronic allograft dysfunction than those with low TGFBeta1 excretion and weak PRA response.. This study demonstrates that some transplant patients with longterm stable graft function show increases in the activities of the TGFBeta system and the RAS. Evaluations of urinary TGFBeta1 excretion and PRA response to ACE-I present a possibility for predicting the development of chronic allograft dysfunction, with significant 4-year predictive values.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Adult; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Chronic Disease; Female; Follow-Up Studies; Humans; Hypertension, Renal; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Renin; Renin-Angiotensin System; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transplantation, Homologous

The renoprotective effect of captopril on progression of diabetic nephropathy was demonstrated by the Collaborative Study Group Captopril Trial and might be independent of blood pressure. Because angiotensin II is known to stimulate the prosclerotic cytokine, transforming growth factor-beta (TGF-beta), we postulated that the renoprotective effect may be due to inhibition of TGF-beta1 production. TGF-beta1 levels were measured in serum at baseline and 6 months from patients in the captopril trial. TGF-beta1 analyses were performed on all available patient sera. Analysis was performed between the percent change in TGF-beta1 levels during the first 6 months versus the percent change in glomerular filtration rate (GFR) in the subsequent 2 years. TGF-beta1 levels increased by 11% (P = 0. 003) in the placebo group (n = 24), whereas there was a decrease of 14% (P = 0.01) in the captopril group (n = 34). There was an inverse correlation between the percent change in TGF-beta1 levels during the first 6 months and the percent change in GFR over the ensuing 2-year period in patients from both the placebo (r = -0.55, P = 0. 005) and captopril groups (r = -0.45, P = 0.008). In patients with initial GFR below 75 mL/min, there was an even stronger correlation in percent change in TGF-beta1 levels and percent change in GFR in both placebo (n = 9, r = -0.69, P = 0.03) and captopril groups (n = 21, r = -0.73, P = 0.0001). Our data suggest that captopril decreases TGF-beta1 levels in diabetic nephropathy and that changes in TGF-beta1 levels may predict the course of diabetic nephropathy.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Captopril; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Female; Follow-Up Studies; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hypertension, Renal; Kidney Function Tests; Male; Transforming Growth Factor beta

Topics: Animals; Desoxycorticosterone Acetate; Fibrosis; Hypertension; Hypertension, Renal; Kidney; Mice; Transforming Growth Factor beta

Renal fibrosis is a crucial pathological feature of hypertensive renal disease (HRD). In-depth analysis of the pathogenesis of fibrosis is of great significance for the development of new drugs for the treatment of HRD. USP25 is a deubiquitinase that can regulate the progression of many diseases, but its function in the kidney remains unclear. We found that USP25 was significantly increased in human and mice HRD kidney tissues. In the HRD model induced by Ang II, USP25

Topics: Angiotensin II; Animals; Deubiquitinating Enzymes; Fibrosis; Humans; Hypertension; Hypertension, Renal; Mice; Signal Transduction; Transforming Growth Factor beta; Ubiquitin Thiolesterase

Hypertensive nephropathy is a chronic kidney disease caused by hypertension. Eicosapentaenoic acid (EPA) has been reported to possess an antihypertensive effect, and our previous study suggested that EPA-enriched phospholipid (EPA-PL) had more significant bioactivities compared with traditional EPA. However, the effect of dietary EPA-PL on hypertensive nephropathy has not been studied. The current study was designed to examine the protection of EPA-PL against kidney damage in spontaneously hypertensive rats (SHRs). Treatment with EPA-PL for three weeks significantly reduced blood pressure through regulating the renin-angiotensin system in SHRs. Moreover, dietary EPA-PL distinctly alleviated kidney dysfunction in SHRs, evidenced by reduced plasma creatinine, blood urea nitrogen, and 24 h proteinuria. Histology results revealed that treatment of SHRs with EPA-PL alleviated renal injury and reduced tubulointerstitial fibrosis. Further mechanistic studies indicated that dietary EPA-PL remarkably inhibited the activation of TGF-β and Smad 3, elevated the phosphorylation level of PI3K/AKT, suppressed the activation of NF-κB, reduced the expression of pro-inflammatory cytokines, including IL-1β and IL-6, and repressed the oxidative stress and the mitochondria-mediated apoptotic signaling pathway in the kidney. These results indicate that EPA-PL has potential value in the prevention and alleviation of hypertensive nephropathy.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Eicosapentaenoic Acid; Fibrosis; Hypertension, Renal; Male; Nephritis; NF-kappa B; Oxidative Stress; Phosphatidylinositol 3-Kinase; Phospholipids; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Renin-Angiotensin System; Signal Transduction; Transforming Growth Factor beta

The Hippo/YAP (yes-associated protein) pathway is an important signaling pathway to control organ development and tissue homeostasis. YAP is a downstream effector of the Hippo pathway and a critical mediator of mechanic stress. Hypertensive nephropathy is characterized with glomerular sclerosis stiffness and renal fibrosis. The present study investigated the role of YAP pathway in angiotensin (Ang) II hypertensive renal injury by using YAP activation inhibitor verteporfin. Ang II increased the protein expression of YAP in renal nucleus fraction, decreased phospho-YAP, and phospho-LATS1/2 (large tumor suppressors 1 and 2) expressions in renal cytoplasmic fraction, suggesting Ang II activation of renal YAP. Ang II significantly increased systolic blood pressure (SBP), proteinuria, glomerular sclerosis, and fibrosis; treatment with verteporfin attenuated Ang II-induced proteinuria and renal injury with a mild reduction in SBP. Moreover, Ang II increased the protein expressions of inflammatory factors including tumor necrosis factor α, interleukin 1β, and monocyte chemoattractant protein-1, and profibrotic factors including transforming growth factor β, phospho-Smad3 and fibronectin. Verteporfin reversed abovementioned Ang II-induced molecule expressions. Our results for the first time demonstrate that the activation of the YAP pathway promotes hypertensive renal inflammation and fibrosis, which may promote hypertensive renal injury. YAP may be a new target for prevention and treatment of hypertensive renal diseases.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Blood Pressure; Chemokine CCL2; Fibrosis; Hypertension; Hypertension, Renal; Male; Mice; Mice, Inbred C57BL; Nephritis; Photosensitizing Agents; Protein Serine-Threonine Kinases; Signal Transduction; Transforming Growth Factor beta; Vasoconstrictor Agents; Verteporfin; YAP-Signaling Proteins

Hypertensive nephropathy, clinically characterized by progressive renal fibrosis and inflammation, is a severe complication of hypertension. The objectives of this study were to investigate the roles of miR-101a in relieving angiotensin II (Ang II)-mediated hypertensive nephropathy and uncover the possible underlying mechanisms. A hypertensive mouse model was established via continuous 28-day AngII infusion. Systolic blood pressure (SBP), ratio of urine albumin to creatinine, blood urea nitrogen (BUN), serum creatinine (Scr) and glomerular filtration rate (GFR) were evaluated. Dual luciferase reporter assay was used to explore the target of miR-101a. mRNA levels of miR-101a, TGFβRI, fibrotic markers (Collagen I and α-SMA) and pro-inflammatory cytokines (IL-1β and TNF-α) were determined by real-time PCR. Protein levels of TGFβRI, Collagen I, α-SMA, IL-1β, TNF-α, t-p65, P-p65, t-Smad3, P-Smad3, t-IκBα and P-IκBα were detected by western blot. MiR-101a mimics significantly improved GFR and inhibited AngII-induced increase in the ratio of urine albumin to creatinine, BUN and Scr. MiR-101a mimics partially abolished AngII-induced increase in the mRNA and protein level of fibrotic markers by targeting TGFβRI and inhibiting TGFβ/Smad3 pathway. Moreover, TGFβRI inhibitor galunisertib inhibited AngII-mediated renal injury in mice with hypertensive nephropathy. Additionally, miR-101a overexpression blocked AngII-induced up-regulation of pro-inflammatory markers via suppressing NF-κB pathway. MiR-101a exhibited protective effects against hypertensive nephropathy via inhibiting TGFβ/Smad3 and NF-κB signalling pathways.

Topics: Angiotensin II; Animals; Base Sequence; Cell Line; Disease Models, Animal; Fibrosis; Hypertension, Renal; Kidney; Male; Mice; MicroRNAs; Nephritis; NF-kappa B; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

Angiotensin-converting enzyme-2 (ACE2) is downregulated in hypertensive nephropathy. The present study investigated the mechanisms whereby loss of ACE2 promoted angiotensin II-induced hypertensive nephropathy in ACE2 gene knockout mice. We found that compared with wild-type animals, mice lacking ACE2 developed much more severe hypertensive nephropathy in response to chronic angiotensin II infusion, including higher levels of blood pressure, urinary protein excretion, serum creatinine, and progressive renal fibrosis and inflammation. Mechanistic studies revealed that worsening kidney injury in ACE2 knockout mice was associated with an increase in Smurf2 (Smad-specific E3 ubiquitin protein ligase 2), a decrease in renal Smad7, and marked activation of TGF-β (transforming growth factor β)/Smad3 and NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling, suggesting that Smurf2-dependent Smad7 ubiquitin degradation may be a key mechanism whereby loss of ACE2 promotes angiotensin II-induced TGF-β/Smad3 and NF-κB-mediated hypertensive nephropathy. This was validated by restoring Smad7 locally in the kidneys of ACE2 knockout mice to block angiotensin II-induced TGF-β/Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation. Moreover, we found that angiotensin II could induce microRNA-21 in the mouse kidney and in cultured mesangial cells via a Smad3-dependent mechanism, which was enhanced by deleting ACE2 but inhibited by overexpressing renal Smad7. In conclusion, loss of ACE2 promotes angiotensin II-induced renal injury by targeting Smad7 for degradation via a Smurf2-dependent mechanism. Overexpression of renal Smad7 protects against hypertensive nephropathy by inactivating angiotensin II-induced TGF-β/Smad3 and NF-κB pathways and by targeting the Smad3-dependent microRNA-21 axis.

Topics: Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Down-Regulation; Fibrosis; Hypertension; Hypertension, Renal; Inflammation; Kidney; Mice; Mice, Knockout; Nephritis; NF-kappa B; Peptidyl-Dipeptidase A; Signal Transduction; Smad1 Protein; Smad7 Protein; Transforming Growth Factor beta; Ubiquitin

Blockade of the renin-angiotensin II (Ang II) system by AT1 blockers (ARBs) and angiotensin-converting enzyme inhibitors retards the progression of chronic kidney disease (CKD) by reducing albuminuria/proteinuria. However, many patients with CKD suffer from residual albuminuria/proteinuria, which is an independent risk factor for CKD progression. The aim of the current study is to investigate the effect of pitavastatin, one of the adjunctive agents to ARBs, on the reduction of albuminuria/proteinuria and further renoprotection mediated by telmisartan in spontaneously hypertensive rats.. Forty-two-week-old spontaneously hypertensive rats were grouped randomly and received 8 weeks of treatments with vehicle, telmisartan, pitavastatin or a combination of telmisartan and pitavastatin. Both albuminuria and proteinuria were inhibited significantly in the telmisartan-treated group, but an obviously residual albuminuria was maintained. The combination treatment with telmisartan and pitavastatin displayed a more effective decrease in albuminuria and proteinuria, even to the normal level. Enhanced nephroprotection was also observed in this combination group, which was independent of the cholesterol-lowering effects. Further mechanistic studies revealed that the combination therapy greatly attenuated the expression of intrarenal Ang II and AT1, thereby decreasing the activation of TGF-β-Smad and NF-κB and inhibiting fibrosis and inflammation.. Adjunctive therapy with pitavastatin dramatically reduced residual albuminuria/proteinuria and enhanced nephroprotection, likely by downregulating the expression of intrarenal Ang II and AT1. It could be concluded that statins might be a promising adjunctive therapeutic agent to conventional ARB treatment in hypertensive renal damage.

Topics: Albuminuria; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Benzoates; Down-Regulation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Renal; Kidney; Male; Nephritis; NF-kappa B; Proteinuria; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Signal Transduction; Telmisartan; Transforming Growth Factor beta

Hypertension is a risk factor for chronic kidney disease, particularly when associated with impaired renal autoregulation and thereby increased intraglomerular pressure (Pgc). Elevated Pgc can be modeled in vitro by exposing glomerular mesangial cells to mechanical strain. We previously showed that RhoA mediates strain-induced matrix production. Here, we show that RhoA activation is dependent on an intact microtubule network. Upregulation of the profibrotic cytokine connective tissue growth factor (CTGF) by mechanical strain is dependent on RhoA activation and inhibited by microtubule disruption. We tested the effects of the microtubule depolymerizing agent colchicine in 5/6 nephrectomized rats, a model of chronic kidney disease driven by elevated Pgc. Colchicine inhibited glomerular RhoA activation and attenuated both glomerular sclerosis and interstitial fibrosis without affecting systemic blood pressure. Upregulation of the matrix proteins collagen I and fibronectin, as well as CTGF, was attenuated by colchicine. Activity of the profibrotic cytokine TGF-β, as assessed by Smad3 phosphorylation, was also inhibited by colchicine. Microtubule disruption significantly decreased renal infiltration of lymphocytes and macrophages. Our studies thus indicate that colchicine modifies hypertensive renal fibrosis. Its protective effects are likely mediated by inhibition of RhoA signaling and renal infiltration of inflammatory cells. Already well-established in clinical practice for other indications, prevention of hypertension-associated renal fibrosis may represent a new potential use for colchicine.

Topics: Animals; Cells, Cultured; Colchicine; Collagen Type I; Connective Tissue Growth Factor; Cytoprotection; Disease Models, Animal; Enzyme Activation; Fibronectins; Fibrosis; Hypertension, Renal; Kidney; Male; Microtubules; Nephrectomy; Nephritis; Phosphorylation; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; rhoA GTP-Binding Protein; Smad3 Protein; Stress, Mechanical; Transfection; Transforming Growth Factor beta

Iron is the most abundant metal in mammalian cells, and plays a pivotal role in many metabolic processes. Dysregulated iron homeostasis is involved in the cause of a number of pathological processes including renal diseases.. Longitudinal MRI scans of salt-loaded spontaneously hypertensive stroke-prone rats (SHRSP), an animal model that spontaneously develops hypertensive nephropathy, showed a decrease in renal and hepatic T2 SI (a sign of iron accumulation) of, respectively, 42.3 ± 2.5% (P < 0.01) and 60.4 ± 15.1% (P < 0.01) in comparison with SHRSP fed a standard diet. This was accompanied by the development of renal inflammation and oxidative stress (as evaluated by immunohistochemical and proteomic analyses), mitochondrial dysfunction, massive proteinuria and sustained intravascular hemolysis with the subsequent depletion of plasma haptoglobin, which was responsible for the renal uptake of hemoglobin and iron accumulation. In order to investigate the role of iron in these pathological processes, we subcutaneously treated the salt-loaded rats with the iron chelator deferoxamine (200 mg/kg per day). The pharmacological treatment prevented iron tissue accumulation, as indicated by the increase in renal and hepatic T2 SI of, respectively, 120.0 ± 10.1% (P < 0.01) and 73.9 ± 4.4% (P < 0.01) in comparison with salt-loaded rats treated with vehicle alone. Deferoxamine also preserved renal morphology and function, the renal infiltration of ED-1-positive macrophages/monocytes, and the expression of MCP-1 and TGF-β mRNA, reduced the level of reactive oxygen species, and improved the activity of mitochondrial cytochrome c oxidase.. These findings suggest that iron dysmetabolism is involved in the development of hypertensive nephropathy in SHRSP.

Topics: Animals; Blood Pressure; Deferoxamine; Disease Models, Animal; Hemolysis; Homeostasis; Hypertension, Renal; Iron; Kidney; Male; Models, Animal; Nephritis; Oxidative Stress; Proteinuria; Proteomics; Rats; Rats, Inbred SHR; Reactive Oxygen Species; Sodium Chloride, Dietary; Stroke; Transforming Growth Factor beta

Pirfenidone (PFD) is a novel anti-fibrotic agent that targets TGFβ. However, the mechanisms underlying its renoprotective properties in hypertension-induced renal injury are poorly understood. We investigated the renoprotective properties of PFD and clarified its renoprotective mechanisms in a rat hypertension-induced renal injury model. Dahl salt-sensitive rats were fed a high-salt diet with or without 1% PFD for 6 weeks. During the administration period, we examined the effects of PFD on blood pressure and renal function. After the administration, the protein levels of renal TGFβ, Smad2/3, TNFα, MMP9, TIMP1, and catalase were examined. In addition, total serum antioxidant activity was measured. Compared to untreated rats, PFD treatment significantly attenuated blood pressure and proteinuria. Histological study showed that PFD treatment improved renal fibrosis. PFD may exert its anti-fibrotic effects via the downregulation of TGFβ-Smad2/3 signaling, improvement of MMP9/TIMP1 balance, and suppression of fibroblast proliferation. PFD treatment also increased catalase expression and total serum antioxidant activity. In contrast, PFD treatment did not affect the expression of TNFα protein, macrophage or T-cell infiltration, or plasma interleukin 1β levels. PFD prevents renal injury via its anti-fibrotic and anti-oxidative stress mechanisms. Clarifying the renoprotective mechanisms of PFD will help improve treatment for chronic renal diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Catalase; Fibrosis; Gene Expression Regulation; Hypertension, Renal; Kidney; Male; Matrix Metalloproteinase 9; Oxidative Stress; Proteinuria; Pyridones; Rats; Rats, Inbred Dahl; Signal Transduction; Smad2 Protein; Smad3 Protein; Sodium Chloride, Dietary; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Transforming growth factor-β (TGF-β) implicated in the pathogenesis of diabetic nephropathy. Hence, developing agents that antagonize fibrogenic signals is a critical issue facing researchers.. Fifty rats were allocated to five groups: 1=control rats, 2=diabetic hypertensive rats 3=diabetic hypertensive rats treated with spironolactone, 4=diabetic hypertensive rats treated with moexpril, 5=diabetic hypertensive rats treated with both spironolactone and moexpril. Measurement of TGF-β, aldosterone, creatinine and ACE. Degree of fibrosis was calculated.. Serum creatinine, mean arterial blood pressure (MAP), aldosterone, ACE, TGF-β and renal fibrosis increased significantly in untreated diabetic hypertensive rats compared with control rats. Administration of spironolactone, moexpril, or both decreased these changes.. Addition of the spironolactone to moexpril was more effective in reducing fibrosis and improvement of renal function than monotherapy with either drug, possibly due to a dual inhibitory effect on the RAS, and thus suppression of TGF-β.

Topics: Animals; Drug Therapy, Combination; Hypertension, Renal; Kidney; Kidney Function Tests; Male; Nephritis; Random Allocation; ras Proteins; Rats; Rats, Wistar; Spironolactone; Tetrahydroisoquinolines; Transforming Growth Factor beta

Advanced renal artery stenosis (RAS) may cause progressive deterioration in renal function. We correlated the histopathological findings and clinical characteristics in selected patients with atherosclerotic RAS who underwent nephrectomy of their small kidneys for resistant renovascular hypertension.. We studied 62 patients who underwent nephrectomy of a small kidney for uncontrolled hypertension between 1990 and 2000.. The mean patient age was 65.4 ± 9.6 years; 28 (45%) were men. Significant tubulointerstitial atrophy with relative glomerular sparing was the predominant pattern of injury in 44 (71%) patients. In 14 (23%) patients, diffuse global glomerulosclerosis was present. The severity of tubulointerstitial atrophy and the extent of glomerulosclerosis were both associated with smaller kidney size (P = 0.002). Three patterns of vascular involvement were present: atheroembolic, atherosclerotic and hypertensive vascular changes, which were documented in 39, 98 and 52% of subjects, respectively. The presence and severity of these vascular changes positively correlated with both atherosclerotic risk factors, such as hypertension, dyslipidaemia and renal insufficiency, and cardiovascular morbidity, including abdominal aortic aneurysm and myocardial infarction. Patients on statin therapy were noted to have less evidence of renal fibrosis as measured by transforming growth factor-beta staining (P = 0.003).. The severity of renal histopathological findings in patients who underwent nephrectomy for resistant hypertension correlated with an increased prevalence of cardiovascular disease, a greater degree of renal dysfunction and more severe dyslipidaemia. Statin therapy may affect development of intra-renal injury by slowing the progression of fibrosis.

Topics: Aged; Arteriosclerosis; Female; Fibrosis; Humans; Hypertension, Renal; Ischemia; Kidney; Male; Middle Aged; Renal Artery Obstruction; Transforming Growth Factor beta

In this study, we tested the hypothesis that long-term Rho-kinase inhibition would reverse nitro-L-arginine methyl ester-exacerbated nephrosclerosis in spontaneously hypertensive rats and attempted to elucidate the mechanism involved.. Five groups (each n = 8) were studied: untreated spontaneously hypertensive rats; nitro-L-arginine methyl ester (50 mg/l in drinking water, for 3 weeks)-treated spontaneously hypertensive rats; nitro-L-arginine methyl ester with fasudil (10 mg/kg/day)-treated spontaneously hypertensive rats; nitro-L-arginine methyl ester for 3 weeks followed by fasudil for 3 weeks-treated spontaneously hypertensive rats (same doses), and nitro-L-arginine methyl ester for 3 weeks followed by untreated for 3 weeks. We examined renal function, blood pressure, histological features, oxidative stress markers, and mRNA expression in the renal cortex.. Nitro-L-arginine methyl ester-treated spontaneously hypertensive rats had higher blood pressure, proteinuria, and serum creatinine and lower creatinine clearance, urinary NO3/NO2 ratio, and urinary cGMP excretion compared with control spontaneously hypertensive rats (all Ps < 0.05). Nitro-L-arginine methyl ester-treated spontaneously hypertensive rats also had increased free radical metabolites and abnormal morphological findings with increased nicotinamide adenine dinucleotide phosphate oxidase activity, phosphorylation of myosin phosphatase targeting subunit-1, and mRNA expression of RhoA, RhoB, RhoC, collagen I and III, transforming growth factor-beta, nicotinamide adenine dinucleotide phosphate subunit, endothelial nitric oxide synthase, plasminogen activator inhibitor, and intercellular adhesion molecule-1 in the renal cortex compared with control spontaneously hypertensive rats. Long-term co-treatment with fasudil slightly improved these indices, but most of them were not statistically significant. Late fasudil treatment significantly improved kidney function, morphological changes, and alterations of mRNA expression in the renal cortex, although late untreated controls did not show any improvement.. These results suggest that Rho-kinase inhibition partly reverses hypertensive glomerulosclerosis. The renoprotective effect of the Rho-kinase inhibitor may have multiple mechanisms including inhibition of extracellular matrix production, oxidative stress, adhesion molecule production, and antifibrinolysis.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Collagen Type I; Collagen Type III; Drug Interactions; Enzyme Inhibitors; Hypertension, Renal; Intercellular Adhesion Molecule-1; Kidney; Male; NADPH Oxidases; Nephrosclerosis; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Plasminogen Activator Inhibitor 1; Protein Kinase Inhibitors; Rats; Rats, Inbred SHR; rho-Associated Kinases; rhoA GTP-Binding Protein; rhoB GTP-Binding Protein; RNA, Messenger; Superoxides; Transforming Growth Factor beta

Chronic kidney disease (CKD) occurs in all age groups, including children. Regardless of the underlying cause, CKD is characterized by progressive scarring that ultimately affects all structures of the kidney. The relentless progression of CKD is postulated to result from a self-perpetuating vicious cycle of fibrosis activated after initial injury. We will review possible mechanisms of progressive renal damage, including systemic and glomerular hypertension, various cytokines and growth factors, with special emphasis on the renin-angiotensin-aldosterone system (RAAS), podocyte loss, dyslipidemia and proteinuria. We will also discuss possible specific mechanisms of tubulointerstitial fibrosis that are not dependent on glomerulosclerosis, and possible underlying predispositions for CKD, such as genetic factors and low nephron number.

Topics: Adolescent; Child; Chronic Disease; Disease Progression; Dyslipidemias; Female; Fibrosis; Genetic Predisposition to Disease; Humans; Hypertension, Renal; Kidney Diseases; Male; Podocytes; Polymorphism, Genetic; Proteinuria; Renin-Angiotensin System; Transforming Growth Factor beta

Hyperinsulinemia has been implicated in the development of diabetic nephropathy. In the present study we compared the renoprotective effects of the thiazolidinedione, pioglitazone (PGZ), to that of insulin in a hypertensive, obese, type II diabetic rat model. PGZ aggravated obesity and gave less glycemic control than insulin. However, renoprotection was markedly better with PZG compared to insulin as shown by lower proteinuria, improved renal function, and less histological evidence of diabetic glomerular and tubulointerstitial lesions. PZG and insulin both reduced renal accumulation of pentosidine and oxidative stress to a similar extent. In contrast, PGZ but not insulin suppressed enhanced transforming growth factor-beta (TGF-beta) expression. We further confirmed in cultured rat proximal tubular cells that insulin enhanced TGF-beta mRNA expression and protein production. Our results identify hyperinsulinemia and the attendant increase of TGF-beta expression as potential therapeutic targets in diabetes independent of glycemic control. This confirms prior clinical evidence that PZG provides renoprotection in obese, diabetic patients with nephropathy.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Glycation End Products, Advanced; Hyperinsulinism; Hypertension, Renal; Hypoglycemic Agents; Insulin; Kidney; Male; Obesity; Oxidative Stress; Pioglitazone; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Thiazolidinediones; Transforming Growth Factor beta

Impaired autoregulation in chronic kidney disease can result in elevation of glomerular capillary pressure and progressive glomerular damage; however, the factors linking chronic glomerular disorders to impaired autoregulation have not been identified. We tested the hypothesis that the cytokine most closely associated with progressive glomerular disease, transforming growth factor (TGF)-beta, may also attenuate autoregulation. Kidneys from normal rats were prepared for videomicroscopy, using the blood-perfused juxtamedullary nephron technique. Autoregulatory responses were measured under control conditions and during superfusion with TGF-beta1 (10 ng/ml). Control afferent arteriolar diameter averaged 18.4 +/- 1 microm and significantly decreased to 16.3 +/- 0.9 and 13.2 +/- 0.8 microm at perfusion pressures of 130 and 160 mmHg, respectively. In the presence of TGF-beta1, autoregulatory responses were completely blocked. In similar experiments performed using PDGF-BB (10 ng/ml) and HGF (25 ng/ml), the normal autoregulatory response was not affected. In vitro studies, using isolated preglomerular vascular smooth muscle cells, revealed that exposure to TGF-beta1 stimulated a rapid increase in reactive oxygen species (ROS) that was inhibited by NADPH oxidase inhibitors. In situ studies, with dihydroethidium staining, revealed a marked increase in renal vessel ROS production on exposure to TGF-beta1. Pretreatment of the juxtamedullary afferent arterioles with tempol, a ROS scavenger, or with apocynin, a NADPH oxidase inhibitor, prevented the impaired autoregulation induced by TGF-beta1. These data reveal a novel hemodynamic pathway by which TGF-beta could lead to progressive glomerular injury by impairing normal renal microvascular function.

Topics: Animals; Arterioles; Feedback, Physiological; Homeostasis; Hypertension, Renal; Kidney Glomerulus; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Renal Circulation; Transforming Growth Factor beta; Transforming Growth Factor beta1

The present study was performed to investigate the effects of the antiallergic drug tranilast on the development of diabetic nephropathy in streptozotocin (50 mg/kg)-induced diabetic spontaneously hypertensive rats (SHR). Diabetic SHR were given standard chow or chow containing tranilast at a dose of 1400 mg/kg for 24 weeks. The effects of tranilast on urinary albumin excretion, mesangial expansion, expression of transforming growth factor-beta (TGF-beta) and type I collagen mRNAs, number of anionic sites on the glomerular basement membrane (GBM), and urinary TGF-beta and 8-hydroxy-2'-deoxyguanosine (8-OHdG) excretion were assessed. Tranilast did not affect the blood glucose concentration or blood pressure in diabetic SHR. Urinary albumin excretion rate and creatinine clearance were markedly increased in diabetic SHR. Tranilast treatment decreased albuminuria and hyperfiltration. Tranilast inhibited the diabetes-induced expansion of mesangial and tuft areas, as well as the increase in urinary TGF-beta and 8-OHdG excretion, loss of anionic sites of GBM, and overexpression of TGF-beta as determined immunohistochemically. The levels of TGF-beta and type I collagen mRNA expression were increased in the renal cortex in untreated diabetic SHR at 24 weeks, as determined by real-time quantitative polymerase chain reaction. Tranilast treatment inhibited the up-regulation of TGF-beta and type I collagen mRNA expression by 65 and 36%, respectively, in diabetic SHR. In conclusion, tranilast decreased albuminuria by suppressing glomerular hyperfiltration, mesangial expansion, and loss of the charge barrier via regulation of extracellular matrix gene expression and oxidative stress. Tranilast may be clinically useful in the treatment of diabetic nephropathy.

Topics: Albuminuria; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Body Weight; Collagen Type I; Diabetic Nephropathies; Disease Progression; Extracellular Matrix Proteins; Filtration; Gene Expression Regulation; Glomerular Mesangium; Hypertension, Renal; Immunohistochemistry; Kidney; Male; Nephrosclerosis; ortho-Aminobenzoates; Rats; Rats, Inbred SHR; RNA, Messenger; Transforming Growth Factor beta

In DOCA-salt hypertension, renal kallikrein levels are increased and may play a protective role in renal injury. We investigated the effect of enhanced kallikrein levels on kidney remodeling of DOCA-salt hypertensive rats by systemic delivery of adenovirus containing human tissue kallikrein gene. Recombinant human kallikrein was detected in the urine and serum of rats after gene delivery. Kallikrein gene transfer significantly decreased DOCA- and salt-induced proteinuria, glomerular sclerosis, tubular dilatation, and luminal protein casts. Sirius red staining showed that kallikrein gene transfer reduced renal fibrosis, which was confirmed by decreased collagen I and fibronectin levels. Furthermore, kallikrein gene delivery diminished myofibroblast accumulation in the interstitium of the cortex and medulla, as well as transforming growth factor (TGF)-beta1 immunostaining in glomeruli. Western blot analysis and ELISA verified the decrease in immunoreactive TGF-beta1 levels. Kallikrein gene transfer also significantly reduced kidney weight, glomerular size, proliferating tubular epithelial cells, and macrophages/monocytes. Reduction of proliferation and hypertrophy was associated with reduced levels of the cyclin-dependent kinase inhibitor p27(Kip1), and the phosphorylation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). The protective effects of kallikrein were accompanied by increased urinary nitrate/nitrite and cGMP levels, and suppression of superoxide formation. These results indicate that kallikrein protects against mineralocorticoid-induced renal fibrosis glomerular hypertrophy, and renal cell proliferation via inhibition of oxidative stress, JNK/ERK activation, and p27(Kip1) and TGF-beta1 expression.

Topics: Animals; Cell Cycle Proteins; Cell Division; Cyclic GMP; Cyclin-Dependent Kinase Inhibitor p27; Desoxycorticosterone; Disease Models, Animal; Extracellular Matrix; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Gene Transfer Techniques; Genetic Therapy; Hypertension, Renal; Hypertrophy; JNK Mitogen-Activated Protein Kinases; Kallikreins; Male; Nitrates; Oxidative Stress; Proteinuria; Rats; Rats, Sprague-Dawley; Sodium Chloride, Dietary; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Suppressor Proteins

Chronic renal disease substantially increases the risk of cardiovascular events and death. Vasopeptidase inhibitors are known to show a strong antihypertensive effect. In the present study, we investigated the nephroprotective potential of the vasopeptidase inhibitor AVE7688 beyond its antihypertensive effects in a mouse model of progressive renal fibrosis.. COL4A3 -/- mice received 25 mg AVE7688 per kg body weight. Treatment was initiated in week 4 (early) and week 7 (late). Eight mice per group were sacrificed after 7.5 or 9.5 weeks, and serum levels of urea, systemic blood pressure, and proteinuria were measured. Renal tissue was investigated by routine histology, electron microscopy, immunohistochemistry, and Western blotting. Lifespan until death from renal fibrosis was monitored.. Lifespan of treated mice increased by 143% (early therapy) and by 53% (late therapy) compared to untreated animals (172 +/- 19 vs. 109 +/- 15 vs. 71 +/- 6 days, P < 0.01). Untreated COL4A3 -/- mice did not develop severe hypertension (mean systolic blood pressure 116 +/- 14 vs. 111 +/- 9 mm Hg in wild-type mice), and both therapies mildly reduced systemic blood pressure (107 +/- 13 and 105 +/- 14 mm Hg, data not significant). AVE7688 decreased proteinuria from 12 +/- 3 g/L in untreated mice to 2 +/- 1 g/L (early) and to 4 +/- 1 g/L (late therapy, P < 0.05), as well as serum-urea from 247 +/- 27 to 57 +/- 10 and to 105 +/- 20 mmol/L (P < 0.05). Extent of fibrosis, inflammation, and profibrotic cytokines was reduced by AVE7688 therapy.. The results indicate a strong nephroprotective effect of the vasopeptidase inhibitor in this animal model of progressive renal fibrosis. Besides the antihypertensive action of AVE7688, its antifibrotic, anti-inflammatory, and antiproteinuric effects demonstrated in the present study may serve as an important therapeutic option for chronic inflammatory and fibrotic diseases in man.

Topics: Animals; Anti-Inflammatory Agents; Autoantigens; Blood Pressure; Collagen Type IV; Connective Tissue Growth Factor; Disease Models, Animal; Extracellular Matrix; Fibrosis; Heterocyclic Compounds, 3-Ring; Hypertension, Renal; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Life Expectancy; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Nephritis, Hereditary; Prodrugs; Protease Inhibitors; Proteinuria; Transforming Growth Factor beta; Transforming Growth Factor beta1

Several salutary biological effects of statins have been described. We sought to investigate more closely the anti-inflammatory and antiproliferative effects of simvastatin (SIMV) in a model of hypertension and progressive renal disease, as well as its effects on the cyclin-cdk inhibitors p21 and p27.. Munich-Wistar rats received the nitric oxide (NO) synthase inhibitor L-NAME (25 mg/kg/day p.o.) for 20 days accompanied by a high-salt diet (HS, 3% Na) and then were kept on HS for 60 days. Animals were then divided into two groups: vehicle (VH) or SIMV 2 mg/kg/day p.o. Albuminuria and tail-cuff pressure were determined at 30 and 60 days. RT-PCR was done to assess renal expression of TGF-beta1, collagen I and III, fibronectin, p27, p21 and monocyte chemoattractant protein-1 (MCP-1). Renal protein expression was assessed by Western blot (proliferating cell nuclear antigen (PCNA)) and immunostaining (macrophage, lymphocyte, PCNA).. SIMV did not prevent the development of severe hypertension or albuminuria. SIMV-treated animals had less severe renal interstitial inflammation and cell proliferation. MCP-1 expression was significantly diminished in the SIMV-treated animals (55.4 +/- 7.3 vs. 84.4 +/- 8.2 OD, p = 0.02). mRNA renal expression for p27 and TGF-beta did not change between groups, but p21 mRNA renal expression, highly induced in this model, significantly decreased with SIMV treatment (31.6 +/- 6.6 vs. 50.2 +/- 5.8 OD, p < 0.05). The interstitial fibrosis score significantly decreased with SIMV (2.46 +/- 0.40 vs. 4.07 +/- 0.38%, p < 0.01), which was confirmed by a decrease in renal collagen I and fibronectin expression. Serum cholesterol level did not change with SIMV.. SIMV attenuated interstitial fibrosis associated with this model of hypertensive renal disease. The mechanism involved MCP-1 downregulation. SIMV treatment was also associated with a p21 downregulation in the kidney, which might be involved in the protection of renal scarring.

Topics: Albuminuria; Animals; Cell Division; Chemokine CCL2; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Disease Models, Animal; Enzyme Inhibitors; Extracellular Matrix; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Renal; Lymphocytes; Macrophages; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Wistar; RNA, Messenger; Simvastatin; Sodium Chloride; Transforming Growth Factor beta

Glomerular capillary hypertension, a common denominator in various forms of progressive glomerular disease, results in mechanical distention of the capillary tuft, and subsequent injury of the overlying podocyte layer. The mechanisms by which elevated intraglomerular pressure is translated into a maladaptive podocyte response remain poorly understood. Angiotensin II plays a central role in the pathogenesis of chronic renal injury, largely through its actions on the subtype 1 receptor. Accordingly, we have tested the hypothesis that mechanical strain up-regulates local angiotensin II in podocytes, thereby resulting in a progressive reduction in podocyte number.. Conditionally immortalized mouse podocytes were subjected to cyclical stretch of 10% amplitude. Nonstretched podocytes served as controls. Angiotensin II levels were measured in whole cell lysate by competitive enzyme-linked immunosorbent assay (ELISA). Expression of angiotensin II receptors (AT1R, AT2R) was measured by quantitative polymerase chain reaction (PCR) and Western blot analysis. Apoptosis was measured by Hoechst staining. Immunostaining for AT1R was performed in tissue sections from rats with 5/6 remnant kidney disease, a model of glomerular hypertension.. Mechanical strain increased angiotensin II production in podocytes at 24, 48, and 72 hours (P < 0.05 vs. nonstretched controls). Stretching podocytes resulted in a fivefold increase in AT1R mRNA expression at 24 hours and a twofold increase in protein levels vs. controls (P < 0.05), and also an increase in transforming growth hormone-beta (TGF-beta) mRNA expression. AT1R staining was increased in a podocyte distribution in the 5/6 remnant kidney, consistent with our in vitro findings. Mechanical strain resulted in a 2.5-fold increase in apoptosis (P < 0.001 vs. nonstretched controls) in an angiotensin II-dependent fashion.. Mechanical strain leads to up-regulation of the AT1R and increased angiotensin II production in conditionally immortalized podocytes. The resulting activation of a local tissue angiotensin system leads to an increase in podocyte apoptosis, mainly in an AT1R-mediated fashion.

Topics: Angiotensin II; Animals; Apoptosis; Capillaries; Cell Line, Transformed; Gene Expression; Hypertension, Renal; Kidney Glomerulus; Mechanotransduction, Cellular; Mice; Rats; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renal Circulation; RNA, Messenger; Stress, Mechanical; Transforming Growth Factor beta; Up-Regulation; Vasoconstrictor Agents

This study was designed to investigate whether chronic angiotensin-converting enzyme (ACE) inhibition prevents hypertensive glomerular injury and inhibits increases in the mRNA levels and immunohistological expression of the apoptosis inducer caspase-3, and transforming growth factor (TGF)-beta 1 during prolonged nitric oxide synthase (NOS) inhibition with N-nitro-L-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHR).. For 3 weeks, we studied three groups of 20-week-old male SHR: a control group, a l-NAME group, and a group treated with L-NAME and the ACE inhibitor imidapril. L-NAME rats developed severe hypertensive nephrosclerosis with significantly elevated blood pressure, markedly increased urinary protein excretion and serum creatinine levels, and more severe glomerulosclerosis and tubulo-interstitial changes. Levels of TGF-beta 1 mRNA in the renal tissue was also significantly increased in L-NAME rats compared with control SHR. Addition of imidapril significantly lowered blood pressure, inhibited nephrosclerosis and attenuated the mRNA level of TGF-beta 1 in comparison with L-NAME/SHR. Histologically, the glomerular cell apoptosis labeling index, terminal doxynucleotidil transferase-mediated dUTP nick-end labeling of fragmented DNA (TUNEL) and active caspase-3, and TGF-beta 1 positive areas were also reduced by imidapril.. These data suggest that imidapril prevents glomerular and arteriolar damages and renal functions, through inhibiting both TGF-beta 1 production and apoptosis induction.

Topics: Animals; Antihypertensive Agents; Aorta; Cardiomegaly; Caspase 3; Caspases; Enzyme Inhibitors; Hypertension, Renal; Imidazolidines; Kidney; Male; Nephrosclerosis; NG-Nitroarginine Methyl Ester; Organ Size; Rats; Rats, Inbred SHR; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

The molecular mechanisms linking abnormal kidney function and obesity hypertension are poorly understood. This study compared gene expression profiles in the kidney medulla and cortex of obese and lean dogs.. Lean dogs (N= 4) were fed a standard kennel ration and obese dogs (N= 4) were fed the standard diet plus 0.5 to 0.9 kg of cooked beef fat per day for 10 weeks. The dogs were instrumented for continuous monitoring of mean arterial pressure (MAP), heart rate, glomerular filtration rate (GFR), and effective renal plasma flow (RPF). The relative mRNA levels of 375 genes in renal cortex and medulla were determined simultaneously using cDNA membrane arrays (R&D Systems).. The high fat diet increased body weight by 57% and MAP increased by 24 mm Hg (112 +/- 1 mm Hg vs. 88 +/- 3 mm Hg) in obese compared to lean dogs. In obese dogs, expression of 11 and 13 genes changed significantly (N= 4; P < 0.05) in the renal medulla and the cortex, respectively, relative to the lean dogs. Differences in renal gene expression profiles between lean and obese dogs were closely related to functional pathways, including those associated with sympathetic activation, inflammatory response, matrix formation, angiogenesis, endothelial dysfunction, attenuated actions of leptin, and attenuated cell survival.. A high fat diet in dogs is associated with marked changes in renal gene expression profiles that provide potential molecular links to pathways associated with altered renal function and structure in obesity hypertension.

Topics: Animals; Blood Pressure; Blotting, Northern; Body Weight; Cytokines; Dogs; Glomerular Filtration Rate; Heart Rate; Hypertension, Renal; Kidney Cortex; Kidney Medulla; Male; Obesity; Oligonucleotide Array Sequence Analysis; Organ Size; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

The present study was designed to clarify whether the Rho-Rho-kinase pathway is involved in the process of hypertensive glomerulosclerosis and to assess the therapeutic effect of fasudil, a specific Rho-kinase inhibitor.. Dahl salt-sensitive rats (DS) and Dahl salt-resistant rats (DR) were fed a high-salt diet at 6 weeks of age. Fasudil (30 mg/kg per day) was administered for 7 weeks to DS starting at the age of 11 weeks. After 7 weeks, untreated DS were characterized by decreased kidney function, increased proteinuria, abnormal morphological findings, increased adrenomedullin and atrial natriuretic peptide (ANP) levels, and increased renal messenger RNA expression of RhoB, Rho-kinasealpha, Rho-kinasebeta, collagen I and collagen III, and transforming growth factor-beta (TGF-beta) in the renal cortex compared with DR. Chronic fasudil treatment significantly improved renal function (serum creatinine, -26%; blood urea nitrogen, -41%; creatinine clearance, +42%), proteinuria (-24%) and histological findings (glomerular injury score, -49%; afferent arteriolar injury score, -17%) without changing blood pressure compared with untreated DS. Interestingly, long-term fasudil treatment decreased the plasma adrenomedullin (-25%) and ANP (-49%), but did not change the plasma renin or aldosterone. Furthermore, fasudil significantly decreased the messenger RNA expression of TGF-beta (-20%), collagen I (-23%), and collagen III (-24%) in the renal cortex. However, there were still significant differences in the aforementioned parameters between DR and fasudil-treated DS.. These results suggest that the Rho-Rho-kinase pathway may be partly responsible for the pathogenesis of hypertensive glomerulosclerosis independently of blood pressure in DS, and that chronic inhibition of the Rho-Rho-kinase pathway may be a new strategy for treating hypertensive nephrosclerosis.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Arterioles; Blood Pressure; Blotting, Western; Collagen Type I; Collagen Type III; Glomerulosclerosis, Focal Segmental; Hypertension, Renal; Intracellular Signaling Peptides and Proteins; Kidney Cortex; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Rats; Rats, Inbred Dahl; rho GTP-Binding Proteins; rho-Associated Kinases; rhoA GTP-Binding Protein; rhoB GTP-Binding Protein; RNA, Messenger; Transforming Growth Factor beta

We have previously shown that abnormal iron metabolism might be one underlying mechanism of the renal damage observed in the angiotensin II-infused rat. Transforming growth factor-beta1 (TGF-beta1) is known to play a crucial role in the development of renal damage induced by activation of the renin-angiotensin-aldosterone system. The purpose of the present study was to examine the effects of an iron chelator and a free radical scavenger on the angiotensin II-induced upregulation of TGF-beta1 in the kidney. Rats were given angiotensin II (0.7 mg/kg/day) via osmotic minipumps for 7 days. The expressions of the mRNAs of TGF-beta1 and collagen types I and IV were significantly increased in response to angiotensin II treatment. Histologic analysis showed that TGF-beta1 expression was upregulated mainly in tubular epithelial cells, and occasionally in glomerular and perivascular cells, some of which were identified as monocytes and/or macrophages. Although tubular cells that overexpressed TGF-beta1 did not contain iron particles, angiotensin II-induced TGF-beta1 upregulation was suppressed by the iron chelator and the free radical scavenger. The free radical scavenger also suppressed angiotensin II-induced upregulation of heme oxygenase-1, an oxidative-stress sensitive gene. By contrast, administration of iron dextran to rats induced upregulation of TGF-beta1 mRNA. Collectively, these data suggest that the renal iron overload and presumed subsequent increase in oxidative stress play a role in angiotensin II-induced upregulation of the mRNAs of TGF-beta1 and collagen types I and IV in the kidney.

Topics: Angiotensin II; Animals; Collagen; Ferritins; Fibrosis; Free Radical Scavengers; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Homeostasis; Hypertension, Renal; Iron; Iron Chelating Agents; Iron Overload; Kidney; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger; Superoxides; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation; Vasoconstrictor Agents

Renal fibrosis is one of the major complications associated with the development of hypertension. The objective of the present study was to determine whether and by which mechanisms treatment with AT1 receptor antagonists makes possible the regression of renal vascular and glomerular fibrosis. Experiments were performed in the hypertensive model of nitric oxide (NO) deficiency in rats. After 4 wk of hypertension, mortality rates averaged 20%; the surviving animals displayed a decline of renal function (urine protein/creatinine, 1.89 +/- 0.63 versus 0.24 +/- 0.03 mg/mmol; creatininemia, 110 +/- 14 versus 38 +/- 2 mmol/L in hypertensive animals and control, respectively; P < 0.01) and an exaggerated gene and protein expression of TGF-beta, collagen I, and collagen IV (P < 0.001) within the renal vasculature associated with the development of glomerulosclerosis (sclerotic index, 2.26 +/- 0.29 versus 0.12 +/- 0.04; P < 0.001). In addition, activities of matrix metalloproteinases 2 and 9 were increased twofold in renal vessels and glomeruli (P < 0.01). Afterwards, losartan, an antagonist of angiotensin receptor type I, or hydralazine were administered in subgroups of hypertensive animals. After 1 wk of angiotensin II antagonism, collagen I, collagen IV, and TGF-beta gene and protein expressions were decreased and glomerulosclerosis was less marked (sclerotic index 1.04 +/- 0.45), whereas activities of metalloproteinases remained twofold higher than controls (P < 0.01). Hydralazine failed to improve renal function despite a similar degree of systolic pressure decrease. After 4 wk of losartan, the renal functional and histologic parameters were completely normalized, whereas they remained damaged in the hypertensive animals in which the mortality rate reached 85%. These data suggest that the progression of renal vascular fibrosis is a reversible process, at least in the NO deficiency model. The mechanism of the regression appears to be dual: inhibition of collagen synthesis due to AT1 receptor antagonism and activation of metalloproteinases that is probably associated with the degree of fibrosis independently of AT1 blockade.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Blood Pressure; Collagen; Enzyme Inhibitors; Fibrosis; Gene Expression; Glomerulosclerosis, Focal Segmental; Hydralazine; Hypertension, Renal; Kidney Glomerulus; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; NG-Nitroarginine Methyl Ester; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Transforming Growth Factor beta

Hypertension of the recipient is strongly associated with chronic allograft nephropathy. It is unclear, however, whether hypertension is the cause or the consequence of chronic allograft nephropathy.. The present study was performed in the Fisher to Lewis rat kidney transplant model. Transplanted rats (N = eight in each group) received either no treatment or were made hypertensive by administration of deoxycorticosteron acetate (DOCA) and salt. Proteinuria and systolic blood pressure was measured monthly, grafts were harvested at 3 and 6 months for semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and for immunohistology.. Systolic blood pressure was markedly elevated in rats receiving DOCA/salt. Allografts of hypertensive animals contained significantly more cells expressing the proliferating cell nuclear antigen compared to isografts and to allografts from normotensive animals (P < 0.05). Histologic staining and mRNA expression of major histocompatibility complex (MHC) II was markedly increased in allografts of hypertensive animals compared to all other groups (P < 0.05). Expression of mRNA for platelet-derived growth factor-B (PDGF-B), transforming growth factor-beta (TGF-beta) and collagen was higher in allografts than in isografts and was highest in hypertensive animals.. We conclude that hypertension augments the expression of growth factors in the allograft possibly aggravating the intimal hyperplasia observed in chronic allograft nephropathy. By increasing the expression of MHC II antigens, hypertension may render the allograft more susceptible to alloantigen-dependent damage. Hypertension and alloantigen-dependent factors appear to exert additive or synergistic effects on inflammatory pathways leading to graft injury.

Topics: Animals; Blood Pressure; Chronic Disease; Desoxycorticosterone; Gene Expression; Graft Rejection; Histocompatibility Antigens Class II; Hypertension, Renal; Kidney Transplantation; Male; Proto-Oncogene Proteins c-sis; Rats; Rats, Inbred F344; Rats, Inbred Lew; RNA, Messenger; Transforming Growth Factor beta; Transplantation, Homologous

Mesangial matrix deposition is the hallmark of hypertensive and diabetic glomerulopathy. At similar levels of systemic hypertension, Dahl salt-sensitive but not spontaneously hypertensive rats (SHR) develop glomerular hypertension, which is accompanied by upregulation of transforming growth factor beta1 (TGF-beta1), mesangial matrix expansion, and sclerosis. GLUT-1 is ubiquitously expressed and is the predominant glucose transporter in mesangial cells. In mesangial cells in vitro, GLUT-1 overexpression increases basal glucose transport, resulting in excess fibronectin and collagen production. TGF-beta1 has been shown to upregulate GLUT-1 expression. We demonstrated that in hypertensive Dahl salt-sensitive (S) rats fed 4% NaCl (systolic blood pressure [SBP]: 236+/-9 mm Hg), but not in similarly hypertensive SHR (SBP: 230+/-10 mm Hg) or their normotensive counterparts (Dahl S fed 0.5% NaCl, SBP: 145+/-5 mm Hg; and Wistar-Kyoto, SBP: 137+/-3 mm Hg), there was an 80% upregulation of glomerular GLUT-1 protein expression (P< or =0.03). This was accompanied by a 2.7-fold upregulation of TGF-beta1 protein expression in glomeruli of DSH compared with DSN rats (P=0.02). TGF-beta1 expression was not upregulated and did not differ in the glomeruli of Wistar-Kyoto and SHR rats. As an in vitro surrogate of the in vivo hemodynamic stress imposed by glomerular hypertension, we used mechanical stretching of human and rat mesangial cells. We found that after 33 hours of stretching, mesangial cells overexpressed GLUT-1 (40%) and showed an increase in basal glucose transport of similar magnitude (both P< or =0.01), which could be blocked with an anti TGF-beta1-neutralizing antibody. These studies suggest a novel link between hemodynamic and metabolic factors that may cooperate in inducing progressive glomerular injury in conditions characterized by glomerular hypertension.

Topics: Animals; Biological Transport; Cells, Cultured; Glomerular Mesangium; Glucose; Glucose Transporter Type 1; Hemodynamics; Humans; Hypertension; Hypertension, Renal; Immunoblotting; Immunohistochemistry; Kidney Cortex; Kidney Glomerulus; Male; Monosaccharide Transport Proteins; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Rats, Inbred WKY; Stress, Mechanical; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

End-stage renal disease (ESRD) is more frequent in African Americans compared to whites. Many factors may be responsible, including genetic differences, increased prevalence of risk factors, and socioeconomic factors; however, to date, these proposed genetic or environmental factors have not provided a satisfactory explanation for the increased risk of ESRD in African Americans. Because renal fibrosis is a correlate of progressive renal failure and a dominant feature of ESRD, and because transforming growth factor beta 1 (TGF-beta1) can induce fibrosis and renal insufficiency, we explored the hypothesis that TGF-beta1 hyperexpression is more frequent in African Americans compared to whites. We tested our hypotheses by measuring TGF-beta1 levels in African Americans and white patients with ESRD, hypertension, and in normal patients. In hypertensive and normal patients, we also evaluated TGF-beta1 mRNA levels, and TGF-beta1 DNA polymorphisms. We demonstrated that circulating levels of TGF-beta1 are higher in African American ESRD patients, hypertensive patients, and normal control patients compared to their white counterparts. We also reported that TGF-beta1 mRNA levels are higher in hypertensives compared to normotensives. Our preliminary genetic analyses suggest that TGF-beta1 DNA polymorphisms may distinguish hypertensives from normotensives, and our laboratory is currently investigating racial differences in TGF-beta1 DNA polymorphisms. Our observations of hyperexpression of TGF-beta1 in African Americans suggest a mechanism for the increased prevalence of renal failure and hypertensive target organ damage in this population.

Topics: Black or African American; Blood Pressure; Female; Humans; Hypertension, Renal; Kidney Failure, Chronic; Linear Models; Male; Middle Aged; Prevalence; Risk Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; White People

Hypertension is the main risk factor for the progression of kidney damage in diabetes mellitus. The aim of the present work is to compare the effect of the treatment with irbesartan (IRBE) and omapatrilat (OMA), in obese Zucker rats (OZR).. A group of 45 OZR were uninephrectomized to accelerate renal damage, and divided into three groups: two experimental groups (IRBE and OMA) treated with 50 and 40 mg/kg/d, respectively; and the control group (CG). At the end of the 8-month follow-up period, animals were killed and the remnant kidney was removed for histologic study and to evaluate the transforming growth factor-beta1 (TGF-beta1) expression.. Both therapies reduced blood pressure (BP) versus CG (P <.001). Moreover, systolic BP was significantly lower in the OMA group than in the IRBE group (P <.001). Also, both treatments significantly lowered the urinary albumin excretion (P <.001). The OMA treatment exhibited lower values than the IRBE treatment (P <.05). The kidney TGF-beta1 expression was reduced by both treatments to a similar level. The correlation between systolic BP and glomerulosclerosis (GS) is very high (r = 0.90; P <.0001). Also, a high correlation was observed between GS and proteinuria (r = 0.79, P <.0001). The correlation between systolic BP and proteinuria was weaker (r = 0.69; P <.01).. These data suggest that both therapies are effective in ameliorating the progression of renal damage in this experimental model. Omapatrilat affords greater long-term renoprotection than irbesartan, mainly due to its potent effect in reducing systolic BP.

Topics: Albuminuria; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Hypertension, Renal; Irbesartan; Kidney; Nephrectomy; Pyridines; Rats; Rats, Zucker; Tetrazoles; Thiazepines; Transforming Growth Factor beta; Transforming Growth Factor beta1

In this study, the relationship between circulating transforming growth factor beta1 (TGFbeta1) and urinary albumin excretion (UAE) has been investigated in non-obese and central obese hypertensive patients.. Fifty-eight consecutive hypertensive outpatients both lean and with central obesity were enrolled and divided in three groups, according to their body mass index (BMI) values. Group A: 16 lean hypertensives (men with BMI < 25 kg/m2 and women with BMI < 24.7 kg/m2); Group B: 16 overweight hypertensives (men with BMI > or = 25 kg/m2 and < 30 kg/m2 and women with BMI > 24.7 kg/m2 and < 27.3 kg/m2); Group C: 26 obese hypertensives (men with BMI > or = 30 kg/m2 and women with BMI > or = 27.3 kg/m2).. In all patients, UAE, by immunonephelometric assay, circulating TGFbeta1 by a solid-phase specific sandwich enzyme-linked immunosorbent assay (ELISA) technique, blood urea nitrogen (BUN) and creatinine, by routine laboratory methods, were determined. In addition, left ventricular telediastolic internal diameter (LVIDd), interventricular septum diastolic (IVSTd), posterior wall thickness (PWT), total and normalized to height2.7 left ventricular mass (LVM, LVM/h2.7), relative wall thickness (RWT) and left ventricular ejection fraction (EF) by M-B Mode echocardiography were calculated.. Overweight and obese hypertensives had significantly (p < 0.05) higher BMI, waist-hip ratio (WHR), UAE and TGFbeta1 than lean hypertensives. Obese hypertensives had significantly (p < 0.05) higher total and indexed LVM values than lean hypertensives. Obese hypertensives had significantly (p < 0.05) higher BMI, UAE and TGFbeta1 than overweight hypertensives. In all subjects, TGFbeta1 correlated directly with BMI (r = 0.52; p < 0.0001), WHR (r = 0.48; p < 0.003), MBP (r = 0.31; p < 0.02) and UAE (r = 0.57; p < 0.0001). Multiple regression analysis indicated that BMI, MBP and UAE were able to explain the 47.9% TGFbeta1 variability (r = 0.69; p < 0.0001), and that TGFbeta1 was the best predictor of UAE changes (r = 0.60; p < 0.0001).. Our data suggest that TGFbeta1 levels are positively associated with BMI, MBP and UAE in hypertensive subjects. This also indicates that TGFbeta1 overproduction might be considered a pathophysiology mechanism of progressive renal function impairment in obese hypertensives.

Topics: Adult; Aged; Albuminuria; Body Mass Index; Body Weight; Electrocardiography; Female; Heart Function Tests; Humans; Hypertension, Renal; Kidney Diseases; Male; Middle Aged; Obesity; Regression Analysis; Transforming Growth Factor beta; Transforming Growth Factor beta1

This study examined the role of transforming growth factor-beta (TGF-beta) in the development of hypertension and renal disease in 9-wk-old male Dahl salt-sensitive (Dahl S) rats fed an 8% NaCl diet for 3 wk. The rats received an intraperitoneal injection of a control or an anti-TGF-beta antibody (anti-TGF-beta Ab) every other day for 2 wk. Mean arterial pressure was significantly lower in Dahl S rats treated with anti-TGF-beta Ab (177 +/- 3 mmHg, n = 12) than in control rats (190 +/- 4 mmHg, n = 17). Anti-TGF-beta Ab therapy also reduced proteinuria from 226 +/- 20 to 154 +/- 16 mg/day. Renal blood flow, cortical blood flow, and creatinine clearance were not significantly different in control and treated rats; however, medullary blood flow was threefold higher in the treated rats than in the controls. Despite the reduction in proteinuria, the degree of glomerulosclerosis and renal hypertrophy was similar in control and anti-TGF-beta Ab-treated rats. Renal levels of TGF-beta1 and -beta2, alpha-actin, type III collagen, and fibronectin mRNA decreased in rats treated with anti-TGF-beta Ab. To examine whether an earlier intervention with anti-TGF-beta Ab would confer additional renoprotection, these studies were repeated in a group of 6-wk-old Dahl S rats. Anti-TGF-beta Ab therapy significantly reduced blood pressure, proteinuria, and the degree of glomerulosclerosis and renal medullary fibrosis in this group of rats. The results indicate that anti-TGF-beta Ab therapy reduces blood pressure, proteinuria, and the renal injury associated with hypertension.

Topics: Anesthesia; Animals; Antibodies, Monoclonal; Blood Pressure; Collagen Type III; Fibronectins; Glomerulosclerosis, Focal Segmental; Hypertension, Renal; Kidney Glomerulus; Male; Proteinuria; Rats; Rats, Inbred Dahl; Renal Circulation; Sodium Chloride, Dietary; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2

Topics: Animals; Animals, Genetically Modified; Hypertension, Renal; Kidney; Proteinuria; Rats; Renal Artery; Renal Veins; Reperfusion Injury; Sirolimus; Time Factors; Transforming Growth Factor beta

Systemic hypertension is a risk factor for progression of renal disease. However, it is not clear whether hypertension has an effect on healing or regression of immune-mediated glomerular damage. To evaluate this effect, we applied a model of glomerulonephritis in rats with two-kidney, one-clip hypertension and studied the effect of hypertension on the healing process of this nephritis.. The anti-thymocyte serum (ATS) glomerulonephritis was induced in rats six weeks after initiation of two-kidney, one-clip hypertension, when blood pressure was already increased. Renal structure and function were examined six weeks later. Glomerular expression of alpha smooth muscle actin, the cell cycle inhibitor p27Kip1, and transforming growth factor-beta (TGF-beta) was evaluated by Western blotting. Glomerular proliferation, monocyte infiltration, and fibronectin were examined by immunohistochemistry.. Decreased survival, an increase of proteinuria, as well as increased glomerular and tubulointerstitial damage, were found in hypertensive rats compared with normotensive rats. Expression of fibronectin, alpha-smooth muscle actin, TGF-beta, and p27Kip1 was increased in the nonclipped kidney. Complete healing of the glomerular changes associated with the nephritis occurred in normotensive nephritic rats. Surprisingly, complete healing of the nephritis was also found in the clipped as well as nonclipped kidneys of renovascular hypertensive rats. No significant differences could be found for survival, proteinuria, glomerular size, proliferation, monocyte/macrophage infiltration, sclerosis, tubulointerstitial damage, as well as expression of alpha-smooth muscle actin, TGF-beta, fibronectin, and p27Kip1 between hypertensive rats with and without nephritis.. These data demonstrate that renovascular hypertension does not influence healing of the glomerular lesions in the anti-thymocyte serum nephritis. This is a rather surprising observation and leaves the question open of which role, in fact, blood pressure may have on the reparative phase of an acute glomerulonephritis, or whether its role depends on the type of glomerulonephritis.

Topics: Animals; Blood Pressure; Cell Cycle Proteins; Cell Division; Cyclin-Dependent Kinase Inhibitor p27; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Hypertension, Renal; Hypertrophy; Immunoglobulin G; Kidney Glomerulus; Macrophages; Male; Microtubule-Associated Proteins; Monocytes; Proteinuria; Rats; Rats, Sprague-Dawley; Survival Analysis; Thymus Gland; Transforming Growth Factor beta; Tumor Suppressor Proteins

The renin-angiotensin system (RAS) is implicated in the development of hypertensive glomerulosclerosis. However, no experimental evidence exists that clearly demonstrates activation of glomerular RAS in hypertensive nephropathy. We used stroke-prone spontaneously hypertensive rats (SHRSP) to examine whether RAS components are increased in glomeruli of SHRSP and whether this increase leads to an increase in mRNA levels for transforming growth factor-beta1 (TGF-beta1).. We examined the sequential changes of urinary albumin excretion (UAE), morphology, and glomerular mRNA expression for TGF-beta1 and fibronectin (FN) in relation to glomerular mRNA expression for angiotensinogen (ATN), angiotensin converting enzyme (ACE), angiotensin II type 1a (AT1a), and type 1b (AT1b) receptors, and intervention with angiotensin II type 1 receptor antagonist candesartan and equihypotensive hydralazine.. In SHRSP, UAE was normal at 9 weeks of age, but became higher, beginning at 12 weeks of age, than that in the age-matched Wistar-Kyoto (WKY) rats, while SHRSP showed no glomerulosclerosis until 14 weeks of age; it was marked at 24 weeks. Plasma renin activity and plasma angiotensin II level was equivalent in the 9- and 12-week-old SHRSP and the WKY rats; both parameters, however, were elevated in 24-week-old SHRSP as compared with age-matched control. RNase protection assays showed that glomerular levels of ATN, ACE, and AT1a and AT1b receptors mRNA were significantly increased in 9-, 12-, and 14-week-old, but not in 24-week-old SHRSP, compared with age-matched WKY rats. Northern blot analysis showed that glomerular levels of TGF-beta1 and FN mRNA were higher in SHRSP than in WKY rats at all time points. Candesartan reduced UAE to control levels, whereas hydralazine reduced UAE but not to control levels. Candesartan administration for 12 weeks virtually prevented the progression of glomerulosclerosis. While candesartan reduced mRNA levels for RAS components, TGF-beta1, and FN to control levels, hydralazine was not effective in this respect. Conclusion Results suggest that increases in glomerular RAS components that occur independently of circulating RAS alter glomerular permselectivity and increase the glomerular expression of TGF-beta1 and FN in young SHRSP. Findings in old SHRSP suggest that altered glomerular permselectivity and an increased glomerular expression of TGF-beta1 and FN may be associated with the activation of systemic RAS.

Topics: Albuminuria; Angiotensin II; Angiotensinogen; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Blotting, Northern; Fibronectins; Gene Expression; Glomerulosclerosis, Focal Segmental; Hydralazine; Hypertension, Renal; Kidney Glomerulus; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Ribonucleases; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Transforming Growth Factor beta1

End-stage renal disease (ESRD) is more frequent in African Americans (blacks) compared to Caucasian Americans (whites). Identification of remediable causes of the increased prevalence has the potential to reduce the excess burden of ESRD. Because renal fibrosis is a correlate of progressive renal failure and a dominant feature of ESRD, and because transforming growth factor-beta 1 (TGF-beta 1) can induce fibrosis and renal insufficiency, we explored the hypothesis that TGF-beta 1 hyperexpression is more frequent in black ESRD patients compared to white ESRD patients. Our postulate was tested by determining circulating levels of TGF-beta 1 protein in the sera of 56 black and 42 white ESRD patients treated by chronic hemodialysis. A solid-phase sandwich enzyme-linked immunosorbent assay, specific for TGF-beta 1, was used to quantify TGF-beta 1 levels in the ESRD cohort. Additional cytokines implicated in tissue repair/remodeling, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), were also measured. Our investigation demonstrated a significantly higher concentration of TGF-beta 1 protein but not that of IL-6 or TNF-alpha in blacks compared to whites. Our observation that TGF-beta 1 is hyperexpressed in black ESRD patients suggests a mechanism for the increased prevalence of renal failure (since TGF-beta 1 hyperexpression can result in renal insufficiency in experimental models) among the black population.

Topics: Black People; Cohort Studies; Female; Gene Expression; Humans; Hypertension, Renal; Interleukin-6; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Prognosis; Risk Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; White People

We previously reported a new animal model of progressive glomerulonephritis induced by a single intravenous injection of the anti-Thy-1 monoclonal antibody MoAb 1-22-3 into uninephrectomized rats (Clin Exp Immunol 102: 181-185, 1995). We examined the effects of angiotensin II (Ang II) receptor antagonist (candesartan) on the clinical features and morphological lesions of this new model. By 10 weeks after induction of nephritis, untreated rats had developed hypertension, massive proteinuria, renal dysfunction, and severe glomerular injury, while uninephrectomized control rats had not. There was a significant increase in levels of glomerular protein and cortical mRNA for transforming growth factor-beta (TGF-beta) and type I and type III collagens in untreated nephritic rats. Ten week treatments with candesartan and hydralazine significantly reduced blood pressure (BP) to an equal extent. Candesartan, but not hydralazine, prevented proteinuria, normalized renal function, and ameliorated glomerular injury. Candesartan also reduced levels of glomerular protein and cortical mRNA for TGF-beta and type I and type III collagens, while hydralazine did not. These findings suggest that candesartan prevents progression to end-stage renal failure by modulating the effects of Ang II at least in part on the production of TGF-beta and type I and type III collagens, and not merely on systemic BP.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Collagen; Glomerular Mesangium; Glomerulonephritis, Membranoproliferative; Hypertension, Renal; Proteinuria; Rats; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta

The expression of transforming growth factor-beta 1 (TGF-beta 1) for hypertensive renal injury was investigated in Dahl salt-sensitive (Dahl-S) rats fed a high-salt (HS; 8% NaCl) diet or a low-salt (LS; 0.3% NaCl) diet for 4 wk. The HS rats developed severe hypertension and renal damage, including glomerulosclerosis and arteriosclerosis. TGF-beta biosynthesis by isolated glomeruli, the TGF-beta localization, and the gene expression of TGF-beta 1, latent TGF-beta binding protein (LTBP), and TGF-beta receptors (Types I, II, and III) were compared between the HS rats and LS rats. A TGF-beta bioassay revealed that the isolated glomeruli from the HS rats secreted a larger amount of latent TGF-beta than those from the LS rats. Northern blotting analysis demonstrated that the HS diet led to the increases in cortical gene expression of TGF-beta 1, LTBP, and TGF-beta receptors, compared with the LS diet. The glomerular biosynthesis of fibronectin and plasminogen activator inhibitor-1 (PAI-1), and cortical mRNA expression for fibronectin, collagen I, and PAI-1 (which may be affected by TGF-beta) in the HS rats were elevated, compared with the LS rats. The latent TGF-beta immunostained by anti-LTBP antibody was localized on the sclerosing glomeruli and vascular walls. Furthermore, fibronectin, collagen I, and PAI-1 were also localized in the sclerotic area. The TGF-beta 1-positive cells, immunostained by antibody for latency-associated peptide of TGF-beta 1, increased in the glomeruli and vascular walls in the HS rats. These results thus suggested that TGF-beta 1 may be related to hypertensive renal injury in this model.

Topics: Animals; Carrier Proteins; Collagen; Diet, Sodium-Restricted; Fibronectins; Gene Expression; Hypertension, Renal; Immunohistochemistry; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Kidney Glomerulus; Latent TGF-beta Binding Proteins; Male; Plasminogen Activator Inhibitor 1; Rats; Receptors, Transforming Growth Factor beta; Sodium Chloride, Dietary; Tissue Distribution; Transforming Growth Factor beta

To investigate the developmental regulation of transforming growth factor-beta 1 (TGF-beta 1) action and the expression of TGF-beta receptors in vascular smooth muscle cells (VSMC) isolated from spontaneously hypertensive rats (SHR).. TGF-beta 1 effects on proliferation and expression of TGF-beta receptor subtypes were compared in VSMC prepared from SHR, Wistar-Kyoto (WKY) and Sprague-Dawley rats of different ages.. TGF-beta 1 effects on platelet-derived growth factor-BB (PDGF-BB)-stimulated proliferation were examined in VSMC isolated from SHR, WKY and Sprague-Dawley rats aged 1, 4 and 12 weeks, and from renal hypertensive WKY rats. TGF-beta receptors on the surface of VSMC were identified by affinity labelling, followed by immunoprecipitation with TGF-beta receptor antibodies; complexes were then analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis.. TGF-beta 1 inhibited by 60-80% PDGF-BB-stimulated proliferation of VSMC from 1-week-old SHR. In 4-week-old SHR, VSMC were resistant to the antiproliferative action of TGF-beta 1, whereas the mitogenic activity of PDGF-BB was increased approximately 150% by TGF-beta 1 in VSMC from 12-week-old SHR. In contrast, TGF-beta 1 inhibited by 10-50% PDGF-BB-stimulated proliferation of VSMC from age-matched WKY and Sprague-Dawley rats. TGF-beta isoforms (TGF-beta 1, -beta 2, -beta 3) all elicited similar growth responses in VSMC from SHR and WKY rats of different ages. Hypertension per se did not alter TGF-beta 1 effects on proliferation, as TGF-beta 1 inhibited by 30-40% growth factor action on VSMC from control, uni-nephrectomized and one-kidney one-clip hypertensive WKY rats. The type I, II and III TGF-beta receptors were expressed on the surface of VSMC isolated from SHR of different ages.. Alterations in TGF-beta 1 responses, which become evident in VSMC from 4-week-old SHR and are most prominent at 12 weeks, may be important in the development of vascular hypertrophy in this rat strain.

Topics: Aging; Animals; Becaplermin; Cell Division; Hypertension, Renal; Male; Muscle Development; Muscle, Smooth, Vascular; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta

We examined the effects of TCV-116, a non-peptide selective AT1 receptor antagonist, on cellular phenotype and on the expression of the transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix genes in the kidneys of stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were given vehicle or TCV-116 (10 mg/kg/day) by gastric gavage for 10 weeks (from the age of 22 to 32 weeks). Renal mRNA levels were measured by Northern blot analysis. In vehicle-treated 32-week-old SHRSP, urinary albumin excretion per 24 h was about 26-fold greater than that in age-matched Wistar-Kyoto (WKY) rats, and the mRNA levels of renal TGF-beta 1, fibronectin and collagen types I and III in SHRSP were all several-fold higher than those in WKY. Immunohistochemical studies showed the prominent presence of alpha-smooth muscle actin-expressing glomerular cells in SHRSP, in contrast to their absence in WKY. Treatment of SHRSP with TCV-116 decreased urinary albumin excretion and renal mRNA levels for TGF-beta 1 and for the above-mentioned extracellular matrix components. TCV-116 prevented the phenotypic modulation of glomerular cells in SHRSP. These results suggest that AT1 receptor antagonists may have powerful renal protective effects.

Topics: Albuminuria; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Cerebrovascular Disorders; Extracellular Matrix; Gene Expression; Hypertension, Renal; Kidney; Kidney Glomerulus; Male; Phenotype; Prodrugs; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Angiotensin; RNA, Messenger; Sclerosis; Tetrazoles; Transforming Growth Factor beta