transforming-growth-factor-beta and Renal-Insufficiency

Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, initially recognized in adipose tissue for its role in fatty acid storage and glucose metabolism. It promotes lipid uptake and adipogenesis by increasing insulin sensitivity and adiponectin release. Later, PPARγ was implicated in cardiac development and in critical conditions such as pulmonary arterial hypertension (PAH) and kidney failure. Recently, a cluster of different papers linked PPARγ signaling with another superfamily, the transforming growth factor beta (TGFβ), and its receptors, all of which play a major role in PAH and kidney failure. TGFβ is a multifunctional cytokine that drives inflammation, fibrosis, and cell differentiation while PPARγ activation reverses these adverse events in many models. Such opposite biological effects emphasize the delicate balance and complex crosstalk between PPARγ and TGFβ. Based on solid experimental and clinical evidence, the present review summarizes connections and their implications for PAH and kidney failure, highlighting the similarities and differences between lung and kidney mechanisms as well as discussing the therapeutic potential of PPARγ agonist pioglitazone.

Topics: Animals; Humans; Kidney; Lung; Pioglitazone; PPAR gamma; Pulmonary Arterial Hypertension; Pulmonary Fibrosis; Renal Insufficiency; Signal Transduction; Transforming Growth Factor beta

Bone morphogenetic protein-7 (BMP7) is a member of the BMP-subfamily of perhaps a dozen proteins within the TGFbeta-superfamily of cysteine-knot fold cytokine-growth factors. BMP7 has pivotal functions during renal and eye development. In adult organisms, BMP7 is heavily expressed in kidney, specifically in podocytes, distal tubules and collecting ducts. The activity of BMP7 is reduced by inhibitors including some members of the dan-cerberus group and CTGF but can be enhanced by endoglin and KCP. Renal BMP7 disappears early in fibrogenic renal diseases which may facilitate progression. Exogenous administration of rhBMP7 or transgenic overexpression reduces renal fibrogenesis and apoptosis as well as transdifferentiation of epithelial cells. BMP7 improves maintenance of nephron function and structural integrity. These antifibrogenic activities result from inhibition of the nuclear translocation of TGFbeta-activated smad3 by smad6 downstream of BMP7-activated smad5. Although at present the beneficial effects of BMP7 have only been studied in rodent models of chronic renal diseases, there is promise for therapeutic utility of rhBMP7 or small molecule BMP7 agonists in patients.

Topics: Bone Morphogenetic Protein 3; Bone Morphogenetic Protein 7; Bone Morphogenetic Protein Receptors; Bone Morphogenetic Proteins; Chronic Disease; Diabetic Nephropathies; Fibrinogen; Gene Expression Regulation; Humans; Inhibins; Kidney; Kidney Diseases; Renal Insufficiency; Transforming Growth Factor beta

The kidney has unique attributes that are related to its complex structure and that affect the nature of fibrogenesis in this organ. It is divided into functional units, called nephrons, that have both a filtering and a reabsorbing component. Sclerosis may initiate in the sites of either of these components but ultimately involves both. The epidemiology and clinical manifestations of renal fibrosis suggest complex genetic and environmental influences on the development of fibrosis. Further, the different structures in the kidney manifest different mechanisms of fibrogenesis. These are determined by a combination of differences in the biology of the affected cells and the physical effects of nephron failure. Although therapy for renal fibrosis remains somewhat problematic, new insights into the mechanisms of the underlying diseases offer the promise of improved approaches to treatment.

Topics: Animals; Basement Membrane; Cell Differentiation; Disease Models, Animal; Fibrosis; Glomerulonephritis; Humans; Kidney Diseases; Nephrons; Rats; Renal Insufficiency; Transforming Growth Factor beta

Topics: Animals; Body Weight; Cell Cycle; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinases; Cyclins; Diet Therapy; Hyperplasia; Hypertrophy; Kidney; Mice; Mice, Knockout; Nephrons; Renal Insufficiency; Transforming Growth Factor beta; Uremia

Topics: Animals; Cell Division; Chemokines; Cytokines; Extracellular Matrix; Fibrosis; Humans; Inflammation; Renal Insufficiency; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Topics: Adult; Aged; Exercise Therapy; Exercise Tolerance; Female; Humans; Male; Middle Aged; Muscle Strength; Myostatin; Quadriceps Muscle; Renal Dialysis; Renal Insufficiency; RNA, Messenger; Somatomedins; 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

Patient-oriented applications of cell culture include cell therapy of organ failure like chronic renal failure. Clinical deployment of a cell-based device for artificial renal replacement requires qualitative and quantitative fidelity of a cultured cell to its

Topics: Animals; Cell Differentiation; Humans; Mammals; Receptors, Transforming Growth Factor beta; Renal Insufficiency; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factors

The prognosis of multiple myeloma (MM) patients combined with renal insufficiency is poor. Renal fibrosis is an important pathological cause for MM patients combined with renal insufficiency. It is reported that epithelial-mesenchymal transition (EMT) of renal proximal tubular epithelial cells is an important mechanism in renal fibrosis. We speculated that EMT might play an important role in the renal insufficiency of MM with unclear mechanism. MM cells derived exosomes could affect the function of targeted cells by delivering microRNAs (miRNAs). Literature has shown that the expression of miR-21 is closely related to EMT. In this research, we found that co-culture of HK-2 cells (human renal proximal tubular epithelial cells) and exosomes derived from MM cells promoted the EMT of HK-2 cells, resulting in the down-regulation of epithelial-related marker (E-cadherin), and up-regulation of stroma-related marker (Vimentin). Meanwhile, the expression of SMAD7, one of the downstream targets in the TGF-β signalling pathway, was suppressed and the expression of TGF-β was increased. After transfecting the inhibitor of miR-21 in MM cells, the expression of miR-21 in exosomes secreted by MM cells was significantly decreased, and the co-culture of these treated exosomes and HK-2 cells inhibited the EMT of HK-2 cells. In conclusion, these findings showed that exosomal miR-21 derived from MM cells could promote renal EMT through targeting TGF-β/SMAD7 signalling pathway.

Topics: Cell Line; Epithelial-Mesenchymal Transition; Fibrosis; Humans; Kidney Diseases; MicroRNAs; Multiple Myeloma; Renal Insufficiency; Smad7 Protein; Transforming Growth Factor beta; Transforming Growth Factor beta1

Although neutrophil elastase (NE) may play a role in lung fibrosis and liver fibrosis, NE involvement in the development of nephrogenic systemic fibrosis has been unclear. We investigated the involvement of NE in the development of nephrogenic systemic fibrosis-like skin lesions post-injections of linear gadolinium-based contrast agents in renal failure mouse models. Renal failure mouse models were randomly divided into three groups: control group (saline), gadodiamide group, and gadopentetate group. Each solution was intravenously administered three times per week for three weeks. The mice were observed daily for skin lesions. Quantification of skin lesions, infiltrating inflammatory cells, and profibrotic cytokines in the affected skin was performed by immunostaining and reverse-transcription polymerase chain reaction (RT-PCR). Blood samples were collected from the facial vein to quantify NE enzymatic activity. The 158Gd concentrations in each sample were quantified using inductively coupled plasma mass spectrometry (ICP-MS). In the gadodiamide group, the mRNA expression of fibrotic markers was increased in the skin lesions compared to the control group. In the gadopentetate group, only collagen 1α and TGF-β mRNA expression were higher than in the control group. The expression of CD3+, CD68+, NE cells and the NE activity in the blood serum were significantly higher in the gadodiamide and gadopentetate groups compared to the control group. Gadolinium concentration in the skin of the gadodiamide group was significantly higher than the gadopentetate group, while almost no traces of gadolinium were found in the control group. Although gadopentetate and gadodiamide affected the fibrotic markers in the skin differently, NE may be involved in the development of fibrosis linked to the GBCAs injections in renal failure mouse models.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; CD3 Complex; Contrast Media; Cytokines; Female; Gadolinium; Leukocyte Elastase; Mice; Nephrogenic Fibrosing Dermopathy; Renal Insufficiency; Skin; Transforming Growth Factor beta

Topics: Age Factors; Animals; Apoptosis; Aquaporin 2; Cell Proliferation; Extracellular Matrix; Failure to Thrive; Fibrosis; Gene Deletion; Genetic Predisposition to Disease; Integrases; Integrin beta1; Kidney Medulla; Kidney Tubules, Collecting; Mice, Knockout; Phenotype; Phosphorylation; Polyuria; Promoter Regions, Genetic; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Renal Insufficiency; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta

Activins are members of the transforming growth factor-beta (TGF-β) superfamily of cytokines. They play critical roles in the onset of acute and chronic inflammatory responses. The aim of this study was to investigate how activin inhibition affects acute kidney injury and inflammation after transplantation. The study was carried out in kidney transplantation and renal ischemia-reperfusion models in the rat. Soluble activin type 2 receptor (sActRIIB-Fc) was used to inhibit activin signaling. Transplantation groups were as follows: (i) cyclosporine A (CsA) (ii) CsA + sActRIIB-Fc, (iii) CsA+ inactive protein control Fc-G1. IRI groups were as follows: (i) no treatment, (ii) sActRIIB-Fc. Serum activin B concentration was significantly elevated after transplantation and IRI, whereas activin A was produced locally in renal allografts. Activin inhibition efficiently limited neutrophil, macrophage, and dendritic cell infiltration to the allografts measured 72 h after transplantation. In addition, sActRIIB-Fc treatment modulated serum cytokine response after transplantation and reduced the early accumulation of fibroblasts in the graft interstitium. In conclusion activin inhibition reduces the innate immune response early after renal transplantation in the rat. It also limits the accumulation of fibroblasts in the graft suggesting that activins may be involved in the fibrogenic signaling already early after kidney transplantation.

Topics: Activins; Allografts; Animals; Cytokines; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Humans; Immunity, Innate; Inflammation; Kidney; Kidney Transplantation; Male; Pilot Projects; Rats; Rats, Wistar; Renal Insufficiency; Reperfusion Injury; Signal Transduction; Time Factors; Transforming Growth Factor beta; Transplantation, Homologous

Renal fibrosis is the final common pathway of a wide variety of chronic kidney diseases. Myofibroblast formation via the differentiation of from tissue-resident fibroblasts and bone marrow-derived mesenchymal stem cells (MSCs), and epithelial-to-mesenchymal transition (EMT) is known to play a pivotal role in the development of renal fibrosis. However, the detailed mechanisms underlying this disorder remain unclear. We herein investigated the role of alpha 2-antiplasmin (α2AP) in myofibroblast formation and the development of renal fibrosis. We observed the development of renal fibrosis using unilateral ureteral obstruction (UUO). α2AP had accumulated in the UUO-induced obstructed kidneys and α2AP deficiency attenuated UUO-induced renal fibrosis in mice. The degree of myofibroblast formation in the obstructed kidneys of α2AP(-/-) mice was less than that in α2AP(+/+) mice. In vitro, α2AP induced myofibroblast formation in renal tubular epithelial cells (RTECs), renal fibrosblasts, and bone marrow-derived mesenchymal stem cells (MSCs). α2AP also induced the production of TGF-β, which is known to be a key regulator of myofibroblast formation and fibrosis. α2AP-induced the TGF-β production was significantly reduced by SP600125, c-Jun N-terminal kinase (JNK) specific inhibitor. Our findings suggest that α2AP induces myofibroblast formation in the obstructed kidneys, and mediates the development of renal fibrosis.

Topics: alpha-2-Antiplasmin; Animals; Anthracenes; Cell Differentiation; Epithelial Cells; Fibrosis; Gene Expression Regulation; Kidney; Male; MAP Kinase Kinase 4; Mesenchymal Stem Cells; Mice; Mice, Knockout; Myofibroblasts; Primary Cell Culture; Protein Kinase Inhibitors; Renal Insufficiency; Signal Transduction; Transforming Growth Factor beta; Ureter; Ureteral Obstruction

Cyclosporine A (CsA) is a potent immunosuppressant used to prevent organ transplant rejection and in the treatment of autoimmune diseases. However, chronic CsA nephropathy is the major limiting factor to its widespread use. The exact mechanisms of CsA-induced renal damage remain to be fully elucidated. The objective of the current research was to examine whether CsA treatment induced any glomerular mesangial cell alterations. In this research goal, human mesangial cells (HMCs) were treated with CsA for various time points. CsA caused an increase in the production of reactive oxygen species (ROS). Microarray analysis of mesangial cells treated with CsA also indicated 282 dysregulated genes. Bioinformatic analysis of these 282 genes indicated enriched apoptotic oxidative stress, mitogen-activated protein kinase (MAPK), and transforming growth factor-β signaling in response to CsA treatment. The focus of this study was directed on oxidative stress and MAPK signaling as potential novel mechanisms of CsA nephrotoxicity. One key contributor to oxidative stress, thioredoxin interacting protein, was significantly upregulated following CsA treatment. Inhibition of the MAPK pathway resulted in attenuation of the CsA-induced mesangial cell alterations. These findings suggest a major role for ROS, oxidative stress, and MAPK signaling in promoting CsA-induced glomerular dysfunction and subsequent nephrotoxicity.

Topics: Apoptosis; Carrier Proteins; Cell Adhesion; Cell Line; Cell Proliferation; Computational Biology; Cyclosporine; Gene Expression Profiling; Gene Expression Regulation; Humans; Immunosuppressive Agents; MAP Kinase Signaling System; Mesangial Cells; Oligonucleotide Array Sequence Analysis; Osmolar Concentration; Oxidative Stress; Reactive Oxygen Species; Renal Insufficiency; Time Factors; Transforming Growth Factor beta

Retrospective chart review.. We reviewed the peri- and postoperative outcomes of our patients who had undergone lumbar and lumbosacral fusion both with and without recombinant human bone morphogenetic protein (rhBMP) over a period of 8 years to assess the frequency of complications and new diagnoses associated with the use of rhBMP2.. Administration of rhBMP2 for augmentation of lumbar and lumbosacral spinal fusion has not previously been associated with systemic complications.. A review of all patients undergoing lumbar and lumbosacral fusion over an 8-year period was performed to determine the frequency of postoperative complications and new diagnoses. Comparisons in complication frequency and new postoperative diagnoses between patients receiving rhBMP2 versus only allo- or autograft were made. Statistical methodology was applied to determine significance. RESULTS.: None of the 105 patients not receiving rhBMP2 and 3 of 24 patients receiving rhBMP2 had blood urea nitrogens and creatinines that more than doubled and reached values >30 and 1.5 mg/dL, respectively, after surgery (P = 0.006). Renal parameters returned to baseline within 45 days of surgery. Two of the 3 patients with postoperative renal insufficiency had been administered 16 mL (24 mg) of rhBMP2, whereas all other patients receiving rhBMP2 had received 8 mL (12 mg). Both of these patients also had supraventricular tachycardia, fever, and mental status changes after surgery. We recorded no significant increase in the incidence of new endocrinologic, autoimmune, neurologic, or neoplastic disorders associated with the use of rhBMP2 in our small patient population.. A small subset of patients may develop transient renal insufficiency after rhBMP2 to augment spinal fusion. Higher doses of rhBMP2 may possibly increase the risk of developing renal insufficiency in particular patients; however, additional study is needed before all the risk factors are understood.

Topics: Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Substitutes; Female; Humans; Lumbar Vertebrae; Male; Recombinant Proteins; Renal Insufficiency; Retrospective Studies; Spinal Fusion; Transforming Growth Factor beta; Treatment Outcome

Kidney transplant recipients that develop signs of renal dysfunction or proteinuria one or more years after transplantation are at considerable risk for progression to renal failure. To assess the kidney at this time, a "for-cause" biopsy is performed, but this provides little indication as to which recipients will go on to organ failure. In an attempt to identify molecules that could provide this information, we used microarrays to analyze gene expression in 105 for-cause biopsies taken between 1 and 31 years after transplantation. Using supervised principal components analysis, we derived a molecular classifier to predict graft loss. The genes associated with graft failure were related to tissue injury, epithelial dedifferentiation, matrix remodeling, and TGF-beta effects and showed little overlap with rejection-associated genes. We assigned a prognostic molecular risk score to each patient, identifying those at high or low risk for graft loss. The molecular risk score was correlated with interstitial fibrosis, tubular atrophy, tubulitis, interstitial inflammation, proteinuria, and glomerular filtration rate. In multivariate analysis, molecular risk score, peritubular capillary basement membrane multilayering, arteriolar hyalinosis, and proteinuria were independent predictors of graft loss. In an independent validation set, the molecular risk score was the only predictor of graft loss. Thus, the molecular risk score reflects active injury and is superior to either scarring or function in predicting graft failure.

Topics: Biopsy; Capillaries; Disease Progression; Forecasting; Glomerular Filtration Rate; Graft Rejection; Humans; Kidney; Kidney Transplantation; Proteinuria; Renal Insufficiency; Transforming Growth Factor beta

Transforming growth factor (TGF)-beta(1), -beta(2), and -beta(3) are involved in control of wound repair and development of fibrosis. Connective tissue growth factor (CTGF) expression is stimulated by all TGF-beta isoforms and is abundant in glomerulosclerosis and other fibrotic disorders. CTGF is hypothesized to mediate profibrotic effects of TGF-beta(1) or to facilitate interaction of TGF-beta(1) with its receptor, but its interactions with TGF-beta isoforms in nonpathological conditions are unexplored so far. Tissue repair and remodeling may recapitulate gene transcription at play in organogenesis. To further delineate the relationship between CTGF and TGF-beta, we compared expression patterns of CTGF and TGF-beta isoforms in rat and human glomerulogenesis and in various human glomerulopathies. CTGF mRNA was present in the immediate precursors of glomerular visceral and parietal epithelial cells in the comma- and S-shaped stages, but not in earlier stages of nephron development. During the capillary loop and maturing glomerular stages and simultaneous with the presence of TGF-beta(1), -beta(2), and -beta(3) protein, CTGF mRNA expression was maximal and present only in differentiating glomerular epithelial cells. CTGF protein was also present on precursors of mesangium and glomerular endothelium, suggesting possible paracrine interaction. Concomitant with the presence of TGF-beta(2) and -beta(3) protein, and in the absence of TGF-beta(1), CTGF mRNA and protein expression was restricted to podocytes in normal adult glomeruli. However, TGF-beta(1) and CTGF were again coexpressed, often with TGF-beta(2) and -beta(3), in particular in podocytes in proliferative glomerulonephritis and also in mesangial cells in diabetic nephropathy and IgA nephropathy (IgA NP). Coordinated expression of TGF-beta isoforms and of CTGF may be involved in normal glomerulogenesis and possibly in maintenance of glomerular structure and function at adult age. Prolonged overexpression of TGF-beta(1) and CTGF is associated with development of severe glomerulonephritis and glomerulosclerosis.

Topics: Animals; Animals, Newborn; Connective Tissue Growth Factor; Diabetic Nephropathies; Disease Models, Animal; Female; Glomerulonephritis; Glomerulonephritis, IGA; Humans; Kidney Glomerulus; Organogenesis; Protein Isoforms; Rats; Rats, Wistar; Renal Insufficiency; RNA, Messenger; Transforming Growth Factor beta

Angiotensin II (Ang II) plays a pivotal role in cardiovascular remodeling leading to hypertension, myocardial infarction, and stroke. Pitavastatin, an HMG-CoA reductase inihibitor, is known to have pleiotropic actions against the development of cardiovascular remodeling. The objectives of this study were to clarify the beneficial effects as well as the mechanism of action of pitavastatin against Ang II-induced organ damage. C57BL6/J mice at 10 weeks of age were infused with Ang II for 2 weeks and were simultaneously administered pitavastatin or a vehicle. Pitavastatin treatment improved Ang II-induced left ventricular hypertrophy and diastolic dysfunction and attenuated enhancement of cardiac fibrosis, cardiomyocyte hypertrophy, coronary perivascular fibrosis, and medial thickening. Ang II-induced oxidative stress, cardiac TGFbeta-1 expression, and Smad 2/3 phosphorylation were all attenuated by pitavastatin treatment. Pitavastatin also reduced Ang II-induced cardiac remodeling and diastolic dysfunction in eNOS-/- mice as in wild-type mice. In eNOS-/- mice, the Ang II-induced cardiac oxidative stress and TGF-beta-Smad 2/3 signaling pathway were enhanced, and pitavastatin treatment attenuated the enhanced oxidative stress and the signaling pathway. Moreover, pitavastatin treatment reduced the high mortality rate and improved renal insufficiency in Ang II-treated eNOS-/- mice, with suppression of glomerular oxidative stress and TGF-beta-Smad 2/3 signaling pathway. In conclusion, pitavastatin exerts eNOS-independent protective actions against Ang II-induced cardiovascular remodeling and renal insufficiency through inhibition of the TGF-beta-Smad 2/3 signaling pathway by suppression of oxidative stress.

Topics: Angiotensin II; Animals; Cardiotonic Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertrophy, Left Ventricular; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type III; Oxidative Stress; Quinolines; Renal Insufficiency; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta; Ventricular Remodeling

We have observed recently that experimental renal failure in the rat is accompanied by increases in circulating concentrations of the cardiotonic steroid, marinobufagenin (MBG), and substantial cardiac fibrosis. We performed the following studies to examine whether MBG might directly stimulate cardiac fibroblast collagen production. In vivo studies were performed using the 5/6th nephrectomy model of experimental renal failure (PNx), MBG infusion (MBG), PNx after immunization against MBG, and concomitant PNx and adrenalectomy. Physiological measurements with a Millar catheter and immunohistochemistry were performed. In vitro studies were then pursued with cultured isolated cardiac fibroblasts. We observed that PNx and MBG increased MBG levels, blood pressure, heart size, impaired diastolic function, and caused cardiac fibrosis. PNx after immunization against MBG and concomitant PNx and adrenalectomy had similar blood pressure as PNx but less cardiac hypertrophy, diastolic dysfunction, and cardiac fibrosis. MBG induced increases in procollagen-1 expression by cultured cardiac fibroblasts at 1 nM concentration. These increases in procollagen expression were accompanied by increases in collagen translation and increases in procollagen-1 mRNA without any demonstrable increase in procollagen-1 protein stability. The stimulation of fibroblasts with MBG could be prevented by administration of inhibitors of tyrosine phosphorylation, Src activation, epidermal growth factor receptor transactivation, and N-acetyl cysteine. Based on these findings, we propose that MBG directly induces increases in collagen expression by fibroblasts, and we suggest that this may be important in the cardiac fibrosis seen with experimental renal failure.

Topics: Animals; Blood Pressure; Bufanolides; Cardiomyopathies; Cells, Cultured; Collagen; Fibroblasts; Fibrosis; Heart; Male; Myocardium; Rats; Rats, Sprague-Dawley; Renal Insufficiency; Signal Transduction; Sodium-Potassium-Exchanging ATPase; Transforming Growth Factor beta; Uremia

Topics: Animals; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Humans; Kidney; Neuroprotective Agents; Renal Insufficiency; Transforming Growth Factor beta

The risk of cardiovascular disease in uremic patients is greater in male than in female patients. Estrogens seem to play a cardioprotective role until menopause. Experimental data on the effect of estrogens on cardiovascular damage are controversial and potential underlying mechanisms especially in renal failure have not been fully clarified.. Three-month-old female uninephrectomized stroke-prone spontaneously hypertensive (SHRsp) rats were sham-operated or ovariectomized. Subsequently, they received either vehicle (sesame oil) or 17-beta-3 benzoate estradiol (E2) (25 microg/day) or estriol (E3) (0.02 mg/day), respectively. After 3 months the animals were sacrified and the organs were harvested using pressure-controlled perfusion fixation. Stereologic parameters such as capillary length density (L(V)), mean intercapillary distance (MID), and volume density of the interstitial tissue (Vv) were quantitated. Additionally, expression of transforming growth factor-beta (TGF-beta), vascular endothelial growth factor (VEGF), flt-1, endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), endothelin A receptor (ETA) receptor, and alpha estrogen receptor was assessed using immunohistochemistry. Intramyocardial capillaries and the aorta were investigated by morphometric methods.. L(V) (mm/mm(3)) was significantly lower (2421 +/- 500) and MID (microm) significantly higher (22.2 +/- 2.33) in vehicle-treated uninephrectomized/ovariectomized compared to uninephrectomized/sham-ovariectomized controls (L(V) 3629 +/- 960, MID 12.7 +/- 2.7) as well as estradiol (L(V) 3340 +/- 739, MID 12.1 +/- 4.96) and estriol (L(V) 4655 +/- 618, MID 14.2 +/- 2.89) treated uninephrectomized/ovariectomized animals. The volume density of the cardiac interstitium was higher in vehicle-treated uninephrectomized/ovariectomized animals compared to uninephrectomized/sham-ovariectomized, estradiol and estriol treated uninephrectomized/ovariectomized rats. The protein level expression of TGF-beta was higher in vehicle treated uninephrectomized/ovariectomized compared to uninephrectomized/sham and all treatment groups.. In ovariectomized SHRsp rats with moderate renal failure cardiac lesions were strikingly less after estradiol or estriol treatment. The results document a beneficial role of estrogens on cardiac abnormalities in a model of moderate renal dysfunction.

Topics: Animals; Aorta; Arterioles; Endothelin-1; Estrogens; Female; Heart; Immunohistochemistry; Myocardium; Nephrectomy; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Ovariectomy; Rats; Rats, Inbred SHR; Renal Insufficiency; RNA, Messenger; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

We have previously reported that N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which is a tetrapeptide hydrolyzed by ACE, inhibits the transforming growth factor-beta (TGF-beta)-induced expression of extracellular matrix proteins via inhibition of the Smad signaling in human mesangial cells. To test in vivo the antifibrotic efficacy of Ac-SDKP, we examined whether long-term Ac-SDKP treatment can prevent renal insufficiency and glomerulosclerosis in diabetic db/db mice. Diabetic db/db mice or nondiabetic db/m mice were treated with Ac-SDKP for 8 weeks using osmotic minipumps. The treatment with Ac-SDKP increased plasma Ac-SDKP concentrations by approximately threefold in both groups but did not affect the blood glucose levels. Histologically, the increased glomerular surface area, mesangial matrix expansion, and overproduction of extracellular matrix proteins in db/db mice were significantly inhibited by Ac-SDKP. Furthermore, Ac-SDKP treatment normalized the increased plasma creatinine value in db/db mice, whereas the albuminuria in Ac-SDKP-treated db/db mice was somewhat decreased as compared with nontreated db/db mice, although the difference was not statistically significant. In addition, the nuclear translocation of Smad3 was inhibited by Ac-SDKP. These results demonstrate that long-term Ac-SDKP treatment ameliorates renal insufficiency and glomerulosclerosis in db/db mice via inhibition of TGF-beta/Smad pathway, suggesting that Ac-SDKP could be useful in the treatment of diabetic nephropathy.

Topics: Animals; Collagen Type IV; Diabetic Nephropathies; DNA-Binding Proteins; Extracellular Matrix Proteins; Fibronectins; Gene Expression; Glomerular Mesangium; Male; Mice; Mice, Knockout; Oligopeptides; Renal Insufficiency; Smad3 Protein; Trans-Activators; Transforming Growth Factor beta

Normal bone tissue is characterised by a balancing of osteoblast and osteoclast activity. The activity and differentiation of these cells are regulated by vitamins, hormones and cytokines. The action of these factors on bone tissue cells depends on the composition and mineralisation of extracellular bone matrix. In particular, transforming growth factor beta 1 (TGFbeta1) acts on collagen fibres, glycosaminoglycan secretion and on the enzymes correlated to the turnover of glycosaminoglycans. The normal functions of bone tissue also depend on its mineralisation, which is highly altered in the process of uraemia.. In this study, we analysed in vitro the effect of transforming growth factor beta on osteoblast proliferation, collagen synthesis and glycosaminoglycan secretion with 3H-thymidine, 3H-proline or 3H-glucosamine incorporation, and on enzymes, such as beta-N-acetyl-D-glucosaminidase and beta-glucuronidase, involved in extracellular matrix turnover. Moreover, phosphatase alkaline activity and osteocalcin related to mineralisation of extracellular matrix were determined.. Our data show that TGFbeta1 significantly decreases 3H-thymidine and 3H-proline incorporation and increases (p < or = 0.01) extracellular sulphated glycosaminoglycan synthesis. It also increases osteocalcin levels, phosphatase alkaline, beta-N-acetyl-D-glucosaminidase and beta-glucoronidase activities.. TGFbeta1 changes the synthesis of extracellular matrix components by osteoblasts. These variations favour the action of cytokine and osteoclasts. Since the TGFbeta1 accumulates in bone tissue and increases during uraemia, with due limitations this action leads to an imbalance between synthesis and degradation and could explain bone alterations in uraemic patients.

Topics: Acetylglucosaminidase; Alkaline Phosphatase; Cell Proliferation; Cells, Cultured; Collagen; Extracellular Matrix; Female; Glucuronidase; Glycosaminoglycans; Humans; Ilium; Osteoblasts; Osteocalcin; Renal Dialysis; Renal Insufficiency; Transforming Growth Factor beta

Patients with type 2 diabetes and macroalbuminuria generally experience progressive glomerular filtration rate (GFR) decline despite angiotensin-converting enzyme inhibition (ACEI) and blood pressure (BP) control but this therapy generally stabilizes GFR in those without macroalbuminuria. Cigarette smoking exacerbates GFR decline in patients with type 2 diabetes and macroalbuminuria despite ACEI and BP control; whether this therapy prevents nephropathy progression in nonmacroalbuminuric type 2 diabetic smokers is unknown.. We determined the course of urine excretion of indices of renal injury that distinguished patients with type 2 diabetes with and without macroalbuminuria but with normal plasma creatinine who were prospectively followed 6 months while receiving ACEI and BP control. We compared this course in nonsmokers and smokers with normo-, micro-, and macroalbuminuria (n = 157) and in response to smoking cessation in a separate cohort (n = 80) with microalbuminuria.. Urine excretion of transforming growth factor beta-1 (UTGFbetaV) increased in macroalbuminuric but not in nonmacroalbuminuric nonsmokers and UTGFbetaV rate was higher in smokers than nonsmokers within each albuminuria group. In the separate microalbuminuric cohort, the rate of UTGFbetaV change for quitting smokers was not different from nonsmokers (0.093 versus -0.123 ng/g of creatine/week, P = not significant) but that for nonquitting smokers (0.970) was higher than nonsmokers (P = 0.017).. Patients with type 2 diabetes who are at high risk compared with low risk for nephropathy progression have progressive renal injury as measured by increasing UTGFbetaV. Cigarette smoking exacerbates renal injury in type 2 diabetes despite BP control and ACEI, but its cessation in those with microalbuminuria ameliorates the progressive renal injury caused by continued smoking.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Collagen Type IV; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Regression Analysis; Renal Insufficiency; Smoking; Smoking Cessation; Transforming Growth Factor beta

Slowly progressive renal injury is the major cause for ESRD. The model of progressive immune complex glomerulonephritis in autoimmune MRL(lpr/lpr) mice was used to evaluate whether chemokine receptor CCR1 blockade late in the disease course can affect progression to renal failure. Mice were treated with subcutaneous injections of either vehicle or BX471, a nonpeptide CCR1 antagonist, three times a day from week 20 to 24 of age [corrected]. BX471 improved blood urea nitrogen levels (BX471, 35.1 +/- 5.3; vehicle, 73.1 +/- 39.6 mg/dl; P < 0.05) and reduced the amount of ERHR-3 macrophages, CD3 lymphocytes, Ki-67 positive proliferating cells, and ssDNA positive apoptotic cells in the interstitium but not in glomeruli. Cell transfer studies with fluorescence-labeled T cells that were pretreated with either vehicle or BX471 showed that BX471 blocks macrophage and T cell recruitment to the renal interstitium of MRL(lpr/lpr) mice. This was associated with reduced renal expression of CC chemokines CCL2, CCL3, CCL4, and CCL5 and the chemokine receptors CCR1, CCR2, and CCR5. Furthermore, BX471 reduced the extent of interstitial fibrosis as evaluated by interstitial smooth muscle actin expression and collagen I deposits, as well as mRNA expression for collagen I and TGF-beta. BX471 did not affect serum DNA autoantibodies, proteinuria, or markers of glomerular injury in MRL(lpr/lpr) mice. This is the first evidence that, in advanced chronic renal injury, blockade of CCR1 can halt disease progression and improve renal function by selective inhibition of interstitial leukocyte recruitment and fibrosis.

Topics: Animals; Autoantibodies; Blood Urea Nitrogen; CD3 Complex; CD8-Positive T-Lymphocytes; Chemokines; Disease Progression; DNA; DNA, Single-Stranded; Fibrosis; Glomerulonephritis; In Situ Hybridization; Ki-67 Antigen; Kidney; Leukocytes; Lupus Nephritis; Lymphocytes; Macrophages; Mice; Mice, Inbred MRL lpr; Microscopy, Fluorescence; Phenylurea Compounds; Piperidines; Receptors, CCR1; Receptors, Chemokine; Renal Insufficiency; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; T-Lymphocytes; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1

Macrophages play an important role in renal interstitial fibrosis via production of transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor-alpha (TNF-alpha); these fibrogenic factors mediate induction of myofibroblastic cells capable of producing extracellular matrices. We investigated the effects of lipopolysaccharide (LPS), a macrophage activator, on the appearance of macrophage populations and subsequent fibrogenesis in cisplatin (CDDP)-induced rat renal lesions. In keeping with the progression of interstitial fibrosis, alpha-smooth muscle actin (alpha-SMA)-immunopositive myofibroblastic cell number began to increase on day 4 and continued gradually until day 16 after CDDP injection. Cells immunoreactive for ED1 (for exudate macrophages), ED2 (for resident macrophages) and ED3 (for activated resident macrophages) showed the highest number on day 4 or day 7, and thereafter, the numbers were gradually decreased up to day 16. On the other hand, the number of cells immunoreactive for OX6 (rat MHC class II-recognizing antibody) was increased on day 7 and remained elevated up to day 16. LPS was injected on day 7 after CDDP injection when the greatest number of ED1-positive macrophages were present. In CDDP/LPS-injected rats, the numbers of macrophages reacting to ED1, ED2, ED3, and OX6 were higher than those in CDDP-injected rats during the observation period between days 7 and 16; ED3- and OX6-positive cells were more prominently increased than ED1- and ED2-postive cells. By RT-PCR analysis, the expression of TGF-beta1 and TNF-alpha mRNAs in CDDP/LPS-injected rats on day 7 was markedly increased in contrast to those in CDDP-injected rats. These findings indicate that LPS treatment enhanced the macrophage expression of fibrogenic factors. However, there was no marked difference in the fibrogenesis between CDDP/LPS- and CDDP-injected rats. These findings suggest that the macrophage populations appearing in CDDP-induced rat renal lesions should be investigated further, to address the complicated pathogenesis of renal interstitial fibrosis.

Topics: Animals; Cisplatin; Fibrosis; Kidney; Lipopolysaccharides; Macrophages; Male; Rats; Rats, Inbred F344; Renal Insufficiency; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

This study assesses the individual contributions of the nonalloreactive factor, cold ischemia (CI), and alloreactivity to late functional and structural renal graft changes, and examines the effect of the association of both factors on the progression of chronic allograft nephropathy. Lewis rats acted as receptors of kidneys from either Lewis or Fischer rats. For CI, kidneys were preserved for 5 hours. The rats were divided into four groups: Syn, syngeneic graft; SynI, syngeneic graft and CI; Allo, allogeneic graft; AlloI, allogeneic graft and CI. Renal function was assessed every 4 weeks for 24 weeks. Grafts were evaluated for acute inflammatory response at 1 week and for chronic histological damage at 24 weeks. Only when CI and allogenicity were combined did immediate posttransplant mortality occur, while survivors showed accelerated renal insufficiency that induced further mortality at 12 weeks after transplant. Solely ischemic rats developed renal insufficiency. Renal structural damage in ischemic rats was clearly tubulointerstitial, while significant vasculopathy and glomerulosclerosis appeared only in the allogeneic groups. There was increased infiltration of macrophages and expression of mRNA-transforming growth factor-beta1 in the ischemic groups, irrespective of the allogeneic background. The joint association of CI plus allogenicity significantly increased cellular infiltration at both early and late stages, aggravating tubulointerstitial and vascular damage considerably. In summary, CI is mainly responsible for tubulointerstitial damage, whereas allogenicity leads to vascular lesion. The association of both factors accelerates and aggravates the progression of experimental chronic allograft nephropathy.

Topics: Animals; Chronic Disease; Cold Temperature; Graft Rejection; Immunohistochemistry; Inflammation; Ischemia; Kidney; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Macrophages; Male; Monocytes; Rats; Rats, Inbred Lew; Renal Insufficiency; RNA, Messenger; Survival Rate; Time; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transplantation, Homologous

Dysbalance in the immune system is perceived as a major factor for adverse outcome after trauma. Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine that regulates proliferation, differentiation of cells, wound healing, and angiogenesis. The influence of TGF-beta1 on trauma patients outcome is still unclear. Injury patterns and clinical outcome parameters of 99 consecutive patients with life-threatening injury and an injury severity score (ISS) > 15 were assessed in a prospective, single-center study at a Level I trauma center. Levels of TGF-beta1 in plasma were measured over a 5-day period by an enzyme-linked immunoabsorbant assay (ELISA). TGF-beta1 plasma levels rise shortly after trauma and gradually drop as the 5th day approaches. Mean and maximal TGF-beta1 plasma levels were significantly higher in patients who developed sepsis and were significantly lower in patients with renal or hepatic failure. Receiver operating characteristics-curve analysis of liver failure shows an area under the curve (AUC) of 0.68 (95%: 0.55-0.81, P = 0.02) and of an AUC of 0.63 (95%: 0.52-0.75, P = 0.03) for renal failure for maximal TGF-beta1 plasma (initial until day 2) levels if lower values represent a more positive test. The data indicate that the increase and decrease of TGF-beta1 plasma levels may contribute to clinical outcome after severe injury. Lower TGF-beta1 levels are associated with liver and renal insufficiency. Higher TGF-beta1 levels 6 h after ICU admission increase the risk of sepsis. TGF-beta1 seems to be an early onset reactant and not a second-line responsive cytokine.

Topics: Accidents, Traffic; Adolescent; Adult; Aged; Area Under Curve; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Injury Severity Score; Liver Failure; Male; Middle Aged; Renal Insufficiency; ROC Curve; Shock, Traumatic; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Trauma Centers; Treatment Outcome; Wound Healing

Alport syndrome (AS) is a common hereditary cause of end-stage renal failure in adolescence due to defects in type IV collagen genes. Molecular genetics allows early diagnosis, however, no preventive strategy can be offered. Using the COL4A3 -/- mouse, an animal model for human AS, we evaluated therapy with ramipril in mice.. One hundred and twenty-two Alport-mice were treated with 10 mg/kg/day ramipril added to drinking water. Proteinuria, serum-urea and lifespan were monitored. Renal matrix was characterized by immunohistochemistry, light- and electron microscopy, and Western blot.. Untreated COL4A3 -/- mice died from renal failure after 71 +/- 6 days. Early therapy starting at four weeks of age and continuing to death delayed onset and reduced the extent of proteinuria. Uremia was postponed by three weeks in treated animals. Lifespan increased by more than 100% to 150 +/- 21 days (P < 0.01). In parallel, decreased deposition of extracellular matrix and lessened interstitial fibrosis as well as reduced amounts of renal transforming growth factor-beta1 (TGF-beta1) could be demonstrated. Late therapy starting at seven weeks decreased proteinuria, however, lifespan did not increase significantly.. The results indicate an antiproteinuric and antifibrotic nephroprotective effect of ramipril in COL4A3 -/- mice is mediated by down-regulation of TGF-beta1. This effect in mice is enhanced by initiation of therapy during pre-symptomatic disease. The data in COL4A3 -/- mice as an animal-model for Alport syndrome suggest that ramipril might as well delay renal failure in humans with AS. Early diagnosis and preemptive treatment also may be crucial in humans.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Autoantigens; Basement Membrane; Collagen Type IV; Disease Models, Animal; Extracellular Matrix; Fibrosis; Kidney; Kidney Glomerulus; Longevity; Mice; Mice, Knockout; Nephritis, Hereditary; Proteinuria; Ramipril; Renal Insufficiency; Transforming Growth Factor beta; Transforming Growth Factor beta1; Uremia

Hepatocyte growth factor (HGF) has mitogenic, morphogenic and anti-apoptotic activities on renal epithelial cells, and is a potential renotropin for renal regeneration. In chronic renal failure/fibrosis, HGF in the kidney declines in a manner reciprocal to the increase in transforming growth factor-beta (TGF-beta). Neutralization of HGF by the antibody leads to acceleration of renal failure/fibrosis, while HGF administration leads to remarkable attenuation, thus indicating the importance of the balance between HGF and TGF-beta in the pathogenesis and therapy of chronic renal failure. HGF is strongly considered as potential treatment for acute and chronic renal failure.

Topics: Animals; Hepatocyte Growth Factor; Humans; Kidney; Mitogens; Renal Insufficiency; Transforming Growth Factor beta

Previous studies demonstrated that 2 mo of dietary supplementation with alpha-lipoic acid (LA) prevented early glomerular injury in non-insulin-treated streptozotocin diabetic rats (D). The present study examined the effects of chronic LA supplementation (30 mg/kg body wt per d) on nephropathy in D after 7 mo of diabetes. Compared with control rats, D developed increased urinary excretion of albumin and transforming growth factor beta, renal insufficiency, glomerular mesangial matrix expansion, and glomerulosclerosis in association with depletion of glutathione and accumulation of malondialdehyde in renal cortex. LA prevented or ameliorated all of these changes in D. Because chronic LA supplementation also attenuated hyperglycemia in D after 3 mo, its effects on renal injury were compared with treatment of rats with sufficient insulin to maintain a level of glycemic control for the entire 7-mo period (D-INS) equivalent to that observed with LA during the final 4 mo. Despite superior longitudinal glycemic control in D-INS, urinary excretion of albumin and transforming growth factor beta, glomerular mesangial matrix expansion, the extent of glomerulosclerosis, and renal cortical malondialdehyde content were all significantly greater, whereas cortical glutathione content was lower than corresponding values in D given LA. Thus, the renoprotective effects of LA in D were not attributable to improved glycemic control alone but also likely reflected its antioxidant activity. The combined antioxidant and hypoglycemic actions of LA both may contribute to its utility in preventing renal injury and other complications of diabetes.

Topics: Albuminuria; Animals; Antioxidants; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Female; Glomerular Mesangium; Glutathione; Hyperglycemia; Hypoglycemic Agents; Kidney Cortex; Malondialdehyde; Rats; Renal Insufficiency; Thioctic Acid; Transforming Growth Factor beta

The secondary hyperparathyroidism of chronic kidney disease (CKD) produces a high turnover osteodystrophy that is associated with peritrabecular fibrosis. The nature of the cells involved in the development of peritrabecular fibrosis may represent osteoprogenitors expressing a fibroblastic phenotype that are retarded from progressing through osteoblast differentiation.. To test the hypothesis that osteoblast differentiation is retarded in secondary hyperparathyroidism due to CKD producing bone marrow fibrosis, we administered bone morphogenetic protein 7 (BMP-7), a physiologic regulator of osteoblast regulation, to C57BL6 mice that had CKD produced by electrocautery of one kidney followed by contralateral nephrectomy two weeks later. Following the second surgical procedure, a subgroup of mice received daily intraperitoneal injections of BMP-7 (10 microg/kg). Three to six weeks later, the animals were sacrificed, blood was obtained for measurements of blood urea nitrogen (BUN) and parathyroid hormone (PTH) levels, and the femora and tibiae were processed for histomorphometric analysis.. The animals had significant renal insufficiency with BUN values of 77.79 +/- 22.68 mg/dL, and the level of renal impairment between the CKD untreated mice and the CKD mice treated with BMP-7 was the same in the two groups. PTH levels averaged 81.13 +/- 51.36 and 75.4 +/- 43.61 pg/mL in the CKD and BMP-7 treated groups, respectively. The animals with CKD developed significant peritrabecular fibrosis. In addition, there was an increase in osteoblast surface and osteoid accumulation as well as increased activation frequency and increased osteoclast surface consistent with high turnover renal osteodystrophy. Treatment with BMP-7 eliminated peritrabecular fibrosis, increased osteoblast number, osteoblast surface, mineralizing surface and single labeled surface. There was also a significant decrease in the eroded surface induced by treatment with BMP-7.. These findings indicate that BMP-7 treatment in the setting of high turnover renal osteodystrophy prevents the development of peritrabecular fibrosis, affects the osteoblast phenotype and mineralizing surfaces, and decreases bone resorption. This is compatible with a role of osteoblast differentiation in the pathophysiology of osteitis fibrosa.

Topics: Animals; Blood Urea Nitrogen; Bone and Bones; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Remodeling; Chronic Kidney Disease-Mineral and Bone Disorder; Fibrosis; Hyperparathyroidism, Secondary; Male; Mice; Mice, Inbred C57BL; Renal Insufficiency; Transforming Growth Factor beta

The present study was designed to examine whether chronic adrenomedullin infusion has renoprotective effects in hypertensive renal failure and the mechanism by which chronic adrenomedullin infusion exerts its effects. Dahl salt-sensitive rats and Dahl salt-resistant rats were fed a high salt diet starting at 6 weeks of age. Recombinant human adrenomedullin or vehicle was infused for 7 weeks in 11-week-old Dahl salt-sensitive rats. Dahl salt-resistant rat was used as a control. After 7 weeks, untreated Dahl salt-sensitive rats were characterized by decreased kidney function, abnormal morphological findings, increased hormone levels, increased renal tissue angiotensin II levels, and altered mRNA expressions of transforming growth factor beta (TGF-beta) and components of the renin-angiotensin system compared with Dahl salt-resistant rats. Chronic adrenomedullin treatment significantly improved renal function (serum creatinine -87%, creatinine clearance +114%, urinary protein excretion -59%) and histological findings (glomerular injury score -54%) without changing mean arterial pressure compared with untreated Dahl salt-sensitive rats. Interestingly, long-term human adrenomedullin infusion decreased the endogenous rat adrenomedullin level (-97%) with a slight increase of human adrenomedullin level. Chronic adrenomedullin treatment also significantly inhibited the increase of plasma renin concentration (-269%), aldosterone level (-82%), and renal tissue angiotensin II levels (-60%). Furthermore, adrenomedullin infusion significantly decreased the increases of mRNA expressions of TGF-beta (- 63%), angiotensin-converting enzyme (-137%), renin (-230%), and angiotensinogen (-38%) in renal cortex. These results suggest that increased endogenous adrenomedullin plays a compensatory role in chronic hypertensive renal failure and that long-term adrenomedullin infusion has renoprotective effects in this type of hypertension model, partly via inhibition of the circulating and renal renin-angiotensin system.

Topics: Adrenomedullin; Angiotensin II; Animals; Creatinine; Drug Implants; Glomerulonephritis; Hormones; Hypertension; Kidney; Male; Peptides; Proteinuria; Rats; Rats, Inbred Dahl; Renal Insufficiency; Renin-Angiotensin System; RNA, Messenger; Sodium Chloride; Time Factors; Transforming Growth Factor beta

Proteinuria is now accepted to be not just a sign of renal disease but also a contributory factor to the development of progressive tubulointerstitial fibrosis. Excellent correlations between the degree of proteinuria and rate of decline of glomerular filtration rate have been demonstrated. What has been investigated less is whether the type of protein found in the urine is important. Using transformed and primary human proximal tubular epithelial cells, we have investigated the binding of albumin and retinol binding protein to plasma membrane preparations and studied the response of the intact cells to increasing concentrations of these same proteins. We have preliminary evidence for differences in the pattern of binding of these two proteins to the plasma membrane receptors and also for differential release of pro-inflammatory cytokines from intact cells. These in vitro results, along with those of other groups, and some recent clinical findings suggest that the quality of proteinuria may play a role in the early development of interstitial fibrosis. Furthermore, the use of such in vitro model systems based on human proximal epithelial cell culture can provide a means of evaluating the potential significance of different markers of tubular damage.

Topics: Cell Line; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-6; Proteinuria; Renal Insufficiency; Retinol-Binding Proteins; Retinol-Binding Proteins, Plasma; Serum Albumin; Transforming Growth Factor beta

Emerging evidence suggests that transforming growth factor-beta (TGF-beta) is an important mediator of diabetic nephropathy. We showed previously that short-term treatment with a neutralizing monoclonal anti-TGF-beta antibody (alphaT) in streptozotocin-diabetic mice prevents early changes of renal hypertrophy and increased matrix mRNA. To establish that overactivity of the renal TGF-beta system mediates the functional and structural changes of the more advanced stages of nephropathy, we tested whether chronic administration of alphaT prevents renal insufficiency and glomerulosclerosis in the db/db mouse, a model of type 2 diabetes that develops overt nephropathy. Diabetic db/db mice and nondiabetic db/m littermates were treated intraperitoneally with alphaT or control IgG, 300 microgram three times per week for 8 wk. Treatment with alphaT, but not with IgG, significantly decreased the plasma TGF-beta1 concentration without decreasing the plasma glucose concentration. The IgG-treated db/db mice developed albuminuria, renal insufficiency, and glomerular mesangial matrix expansion associated with increased renal mRNAs encoding alpha1(IV) collagen and fibronectin. On the other hand, treatment with alphaT completely prevented the increase in plasma creatinine concentration, the decrease in urinary creatinine clearance, and the expansion of mesangial matrix in db/db mice. The increase in renal matrix mRNAs was substantially attenuated, but the excretion of urinary albumin factored for creatinine clearance was not significantly affected by alphaT treatment. We conclude that chronic inhibition of the biologic actions of TGF-beta with a neutralizing monoclonal antibody in db/db mice prevents the glomerulosclerosis and renal insufficiency resulting from type 2 diabetes.

Topics: Animals; Antibodies, Monoclonal; Carrier Proteins; Diabetes Mellitus, Type 2; Disease Models, Animal; Extracellular Matrix; Extracellular Matrix Proteins; Glomerular Mesangium; Mice; Mice, Mutant Strains; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Cell Surface; Receptors, Leptin; Receptors, Transforming Growth Factor beta; Renal Insufficiency; Transforming Growth Factor beta; Up-Regulation

Topics: Biological Transport; Blood Glucose; Diabetic Nephropathies; Humans; Hyperglycemia; Immediate-Early Proteins; Nuclear Proteins; Protein Serine-Threonine Kinases; Renal Insufficiency; Sodium; Transforming Growth Factor beta

Patients with posterior urethral valves (PUV) are at significant risk for progression to end-stage renal disease, despite early correction of the obstruction. Experimental models of urinary obstruction demonstrate increased renal expression of the profibrotic inflammatory mediator, transforming growth factor-beta(1) (TGF-beta(1)). Urinary TGF-beta(1) excretion is elevated in certain glomerular diseases, but has not been well studied in patients with obstructive lesions. The objective of this study was to examine urinary TGF-beta(1) excretion in children with PUV.. Fourteen patients with PUV, aged 3.2 to 14.5 years, with estimated glomerular filtration rates (GFRs) of 12.8 to 139 mL/min/1.73 m(2) were enrolled. Sixteen normal subjects (9 male, 7 female), aged 4.3 to 20.5 years, served as controls. Total urinary TGF-beta(1) concentration was assayed by enzyme-linked immunoabsorbent assay, and expressed as a ratio to urinary creatinine concentration.. Urinary TGF-beta(1) excretion was significantly greater in patients with PUV (range 0 to 0.063, median 0.019 ng/mg urine creatinine) compared with that of healthy controls (range 0 to 0.022, median 0.005 ng/mg urine creatinine) (P <0.01). There was no correlation between urinary TGF-beta(1) excretion and estimated GFR, past urinary diversion surgery, or bladder wall thickening. Among healthy controls, urinary TGF-beta(1) was not correlated with age or gender.. Results from this study suggest that TGF-beta(1) may contribute to progressive renal insufficiency in patients with PUV. Further studies are indicated to determine if agents that affect TGF-beta(1) expression, such as angiotensin-converting enzyme inhibitors, can slow the progression of renal disease in PUV.

Topics: Adolescent; Adult; Age Factors; Child; Child, Preschool; Creatinine; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Pilot Projects; Renal Insufficiency; Sex Factors; Transforming Growth Factor beta; Urethra; Urethral Obstruction

To determine whether genetic factors are involved in the development of renal dysfunction due to cyclosporine nephrotoxicity, we analyzed 2 polymorphisms in the signal sequence of the transforming growth factor (TGF)-beta 1 gene; codon 10 (Leu(10) --> Pro) and codon 25 (Arg(25) --> Pro).. Using sequence specific oligonucleotide probing, we analyzed both TGF-beta1 gene polymorphisms in cardiac allograft recipients (n = 168) who survived at least 1 year with minimal follow-up of 7 years. Patients received cyclosporine and steroids as maintenance immunosuppressive therapy. Renal dysfunction was defined as a serum creatinine > or = 250 micromol/liter.. Renal dysfunction was observed in 2% (3/168) of the patients at 1 year, in 7% (11/160) at 3 years, in 12% (18/152) at 5 years, and in 20% (26/131) at 7 years post-transplantation. The genotypic distributions for TGF-beta1 codon 10 were 7% Pro/Pro, 61% Pro/Leu, and 32% Leu/Leu, and for codon 25 these percentages were 1% Pro/Pro, 12% Pro/Arg, and 87% Arg/Arg. We found an association between the TGF-beta 1 genotype encoding proline at codon 10 and renal dysfunction. At 7 years post-transplantation, 26% (23/89) of the patients with the heterozygous Pro/Leu or homozygous Pro/Pro genotype had renal dysfunction vs only 7% (3/42) of the patients with the homozygous Leu/Leu genotype (p = 0.017). For the TGF-beta1 codon 25 genotypes, we found no association between TGF-beta 1 genotypes and renal dysfunction.. Our data support the hypothesis that TGF-beta 1 is involved in the process leading to renal insufficiency in cyclosporine-treated cardiac allograft recipients. In these patients the presence of TGF-beta 1 Pro(10) might be a risk factor.

Topics: Adult; Cyclosporine; Female; Genotype; Heart Transplantation; Humans; Immunosuppressive Agents; Leucine; Male; Middle Aged; Polymorphism, Genetic; Proline; Renal Insufficiency; Sequence Analysis, DNA; Transforming Growth Factor beta

The renin-angiotensin system (RAS) and endothelin system may both play a role in the pathogenesis of progressive renal injury. The aims of the present study were 3-fold: first, to explore the possible benefits of dual blockade of the RAS with an ACE inhibitor and an angiotensin type 1(AT1) receptor antagonist; second, to examine the relative efficacy of endothelin A receptor antagonism (ETA-RA) compared with combined endothelin A/B receptor antagonism (ETA/B-RA); and third, to assess whether interruption of both RAS and endothelin system had any advantages over single-system blockade. Subtotally nephrectomized rats were studied as a model of progressive renal injury and randomly assigned to one of the following treatments for 12 weeks: perindopril (ACE inhibitor), irbesartan (AT1 receptor antagonist), BMS193884 (ETA-RA), bosentan (ETA/B-RA), and a combination of irbesartan with either perindopril or BMS193884. Treatment with irbesartan or perindopril was associated with an improved glomerular filtration rate and reductions in blood pressure, urinary protein excretion, glomerulosclerosis, and tubular injury in association with reduced gene expression of transforming growth factor-beta(1) and matrix protein type IV collagen. The combination of irbesartan with perindopril was associated with further reductions in blood pressure and urinary protein excretion. No beneficial effects of either BMS193884 or bosentan were noted. Furthermore, the addition of BMS193884 to irbesartan did not confer any additional benefits. These findings suggest that the RAS but not the endothelin system is a major mediator of progressive renal injury after renal mass reduction and that the combination of an AT1 receptor antagonist with an ACE inhibitor may have advantages over the single agent of RAS blocker treatment.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Collagen; Disease Models, Animal; Disease Progression; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelin-1; Glomerular Filtration Rate; Kidney; Male; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, Endothelin A; Receptor, Endothelin B; Renal Insufficiency; Renin-Angiotensin System; RNA, Messenger; Severity of Illness Index; Transforming Growth Factor beta

Topics: Black or African American; Blood Pressure; Gene Expression Regulation; Humans; Hypertension; Kallikreins; Polymorphism, Genetic; Promoter Regions, Genetic; Renal Insufficiency; Risk Factors; Transforming Growth Factor beta; United States; White People