angiotensin-i and Proteinuria

Rapidly progressive crescentic glomerulonephritis associated with anti-neutrophil cytoplasmic antibodies (ANCA-GN) is a major cause of renal failure. Current immunosuppressive therapies are associated with severe side effects, intensifying the need for new therapeutic strategies. The activation of Mas receptor/Angiotensin-(1-7) axis exerted renoprotection in chronic kidney disease. Here, we investigated the effect of adding the lanthionine-stabilized cyclic form of angiotensin-1-7 [cAng-(1-7)] to cyclophosphamide in a rat model of ANCA-GN. At the onset of proteinuria, Wistar Kyoto rats with ANCA-GN received vehicle or a single bolus of cyclophosphamide, with or without daily cAng-(1-7). Treatment with cAng-(1-7) plus cyclophosphamide reduced proteinuria by 85% vs. vehicle, and by 60% vs. cyclophosphamide, and dramatically limited glomerular crescents to less than 10%. The addition of cAng-(1-7) to cyclophosphamide protected against glomerular inflammation and endothelial rarefaction and restored the normal distribution of parietal epithelial cells. Ultrastructural analysis revealed a preserved GBM, glomerular endothelium and podocyte structure, demonstrating that combination therapy provided an additional layer of renoprotection. This study demonstrates that adding cAng-(1-7) to a partially effective dose of cyclophosphamide arrests the progression of renal disease in rats with ANCA-GN, suggesting that cAng-(1-7) could be a novel clinical approach for sparing immunosuppressants.

Topics: Angiotensin I; Animals; Antibodies, Antineutrophil Cytoplasmic; Cyclophosphamide; Glomerulonephritis; Peptide Fragments; Proteinuria; Rats; Rats, Inbred WKY

Topics: Actins; Adult; Angiotensin I; Animals; Blood Pressure; Cell Line; Down-Regulation; Female; Humans; Hypertension, Pregnancy-Induced; Membrane Proteins; Mice; Peptide Fragments; Podocytes; Pre-Eclampsia; Pregnancy; Proteinuria; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Zonula Occludens-1 Protein

This study was designed to explore the effect of angiotensin 1-7 (Ang 1-7) on experimentally induced-preeclampsia in Wistar rats targeting the role of peroxisome proliferator-activated receptors gamma expression (PPARs-γ) & asymmetric dimethylarginine (ADMA). 30 female Wistar rats were divided into three groups: Normal pregnant (NP), preeclampsia (PE), and preeclampsia treated with Ang 1-7 (PE + Ang 1-7) groups. Reduced uterine perfusion pressure (RUPP) model was induced on GD14. On GD18, protein in urine, urine volume and urinary sodium excretion were determined. On GD19, the systolic blood pressure (SBP) was measured, and the gene expression of PPARs-γ were determined. The serum samples were separated for determination of Ang 1-7, ADMA, soluble fms-like tyrosine kinase (sFlt-1), vascular endothelial growth factor (VEGF), nitric oxide (NO) products, endothelial nitric oxide synthase (eNOS) activity, interleukin-6 (IL-6), interleukin-10 (IL-10), malondialdehyde (MDA), and total anti-oxidant capacity (T-AOC). Compared to NP group, SBP, urine protein, serum levels of ADMA, sFlt-1, IL-6 and MDA significantly increased, while expression of PPARs-γ, serum levels of Ang 1-7, VEGF, NO products, eNOS, IL-10 and T-AOC significantly decreased in PE group, while treatment of Ang 1-7 significantly ameliorated all these studied parameters as compared to PE group. We concluded that Ang 1-7 attenuated the symptoms of preeclampsia, which might be via increasing the expression of PPARs-γ and reduction of ADMA levels which could explain its anti-hypertensive, anti-angiogenic, anti-inflammatory and antioxidant effects.

Topics: Angiotensin I; Animals; Arginine; Blood Pressure; Female; Oxidative Stress; Peptide Fragments; Placenta; PPAR gamma; Pre-Eclampsia; Pregnancy; Proteinuria; Rats, Wistar; Sodium

The Renin-Angiotensin System (RAS) possesses a counter-regulatory axis composed of angiotensin converting enzyme (ACE)2, angiotensin-(1-7) [Ang-(1-7)] and the Mas receptor, which opposes many AT1-receptor-mediated effects of ligand angiotensin II. Ang-(1-7), as a ligand of the Mas receptor, has inhibitory effects on renal inflammation and fibrosis in experimental diabetes. However, Ang-(1-7) has a short half-life in plasma, which may render it unsuitable for use in clinics. Here, we investigated the effects of the lanthionine-stabilized Ang-(1-7), cyclic (c)Ang-(1-7), a lanthipeptide that is more peptidase-resistant than the linear peptide, in BTBR ob/ob mice with type 2 diabetic nephropathy. BTBR ob/ob mice received vehicle, cAng-(1-7), or the ACE inhibitor lisinopril. The treatment started at ten weeks of age, when the animals had already developed albuminuria, and ended at 19-20 weeks of age. cAng-(1-7) limited albuminuria progression, and limited podocyte dysfunction similarly to lisinopril. cAng-(1-7), unlike lisinopril, reduced glomerular fibrosis and inflammation, and counteracted glomerular capillary rarefaction. Furthermore, when cAng-(1-7) was combined with lisinopril, a superior antiproteinuric effect than with lisinopril alone was found, in association with better preservation of podocyte proteins and amelioration of capillary density. Thus, adding cAng-(1-7) to ACE-inhibitor therapy could benefit those diabetic patients who do not respond completely to ACE-inhibitor therapy.

Topics: Alanine; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Drug Therapy, Combination; Half-Life; Humans; Kidney Glomerulus; Lisinopril; Male; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Peptide Fragments; Peptides, Cyclic; Proteinuria; Sulfides

Prenatal glucocorticoid administration in clinically relevant doses reduces nephron number and renal function in adulthood and is associated with hypertension. Nephron loss in early life may predispose the kidney to other insults later but whether sex influences increases in renal susceptibility is unclear. Therefore, we determined, in male and female adult sheep, whether antenatal glucocorticoid (betamethasone) exposure increased 8-isoprostane (marker of oxidative stress) and protein excretion after acute nephron reduction and intrarenal infusions of angiotensin peptides. We also examined whether renal proximal tubule cells (PTCs) could contribute to alterations in 8-isoprostane excretion in a sex-specific fashion. In vivo, ANG II significantly increased 8-isoprostane excretion by 49% and protein excretion by 44% in male betamethasone- but not in female betamethasone- or vehicle-treated sheep. ANG-(1-7) decreased 8-isoprostane excretion but did not affect protein excretion in either group. In vitro, ANG II stimulated 8-isoprostane release from PTCs of male but not female betamethasone-treated sheep. Male betamethasone-exposed sheep had increased p47 phox abundance in the renal cortex while superoxide dismutase (SOD) activity was increased only in females. We conclude that antenatal glucocorticoid exposure enhances the susceptibility of the kidney to oxidative stress induced by ANG II in a sex-specific fashion and the renal proximal tubule is one target of the sex-specific effects of antenatal steroids. ANG-(1-7) may mitigate the impact of prenatal glucocorticoids on the kidney. P47 phox activation may be responsible for the increased oxidative stress and proteinuria in males. The protection from renal oxidative stress in females is associated with increased SOD activity.

Topics: Angiotensin I; Angiotensins; Animals; Betamethasone; Dinoprost; Female; Glucocorticoids; Kidney; Male; NADPH Oxidases; Oxidative Stress; Peptide Fragments; Pregnancy; Prenatal Exposure Delayed Effects; Proteinuria; Sex Factors; Sheep; Superoxide Dismutase

The urinary angiotensinogen (AGT) excretion rate could be a novel biomarker for the intrarenal activity of the renin-angiotensin system. Little is known about the circadian rhythm of AGT levels in plasma or urine. In this short article, making use of data in plasma and urine of healthy volunteers and patients with chronic kidney diseases, we first report that we were unable to find evidence for a circadian rhythm of AGT under any condition. Next we critically discuss to what degree elevated urinary AGT levels might be considered an independent biomarker that is not simply the non-specific consequence of proteinuria.

Topics: Adult; Angiotensin I; Angiotensinogen; Biomarkers; Circadian Rhythm; Enzyme-Linked Immunosorbent Assay; Female; Healthy Volunteers; Humans; Male; Proteinuria; Renal Insufficiency, Chronic

Angiotensin (ANG)-(1-7) is known to attenuate diabetic nephropathy; however, its role in the modulation of renal inflammation and oxidative stress in type 2 diabetes is poorly understood. Thus in the present study we evaluated the renal effects of a chronic ANG-(1-7) treatment in Zucker diabetic fatty rats (ZDF), an animal model of type 2 diabetes and nephropathy. Sixteen-week-old male ZDF and their respective controls [lean Zucker rats (LZR)] were used for this study. The protocol involved three groups: 1) LZR + saline, 2) ZDF + saline, and 3) ZDF + ANG-(1-7). For 2 wk, animals were implanted with subcutaneous osmotic pumps that delivered either saline or ANG-(1-7) (100 ng·kg(-1)·min(-1)) (n = 4). Renal fibrosis and tissue parameters of oxidative stress were determined. Also, renal levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), ED-1, hypoxia-inducible factor-1α (HIF-1α), and neutrophil gelatinase-associated lipocalin (NGAL) were determined by immunohistochemistry and immunoblotting. ANG-(1-7) induced a reduction in triglyceridemia, proteinuria, and systolic blood pressure (SBP) together with a restoration of creatinine clearance in ZDF. Additionally, ANG-(1-7) reduced renal fibrosis, decreased thiobarbituric acid-reactive substances, and restored the activity of both renal superoxide dismutase and catalase in ZDF. This attenuation of renal oxidative stress proceeded with decreased renal immunostaining of IL-6, TNF-α, ED-1, HIF-1α, and NGAL to values similar to those displayed by LZR. Angiotensin-converting enzyme type 2 (ACE2) and ANG II levels remained unchanged after treatment with ANG-(1-7). Chronic ANG-(1-7) treatment exerts a renoprotective effect in ZDF associated with a reduction of SBP, oxidative stress, and inflammatory markers. Thus ANG-(1-7) emerges as a novel target for treatment of diabetic nephropathy.

Topics: Acute-Phase Proteins; Angiotensin I; Animals; Blood Pressure; Diabetic Nephropathies; Fibrosis; Hypertriglyceridemia; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-6; Kidney; Lipocalin-2; Lipocalins; Male; Oxidative Stress; Peptide Fragments; Proteinuria; Proto-Oncogene Proteins; Rats; Rats, Zucker; Tumor Necrosis Factor-alpha

Angiotensin (ANG)-(1-7) constitutes an important functional end-product of the renin-angiotensin-aldosterone system that acts to balance the physiological actions of ANG II. In the kidney, ANG-(1-7) exerts beneficial effects by inhibiting growth-promoting pathways and reducing proteinuria. We examined whether a 2-wk treatment with a daily dose of ANG-(1-7) (0.6 mg·kg(-1)·day(-1)) exerts renoprotective effects in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). Body weight, glycemia, triglyceridemia, cholesterolemia, as well as plasma levels of Na+ and K+ were determined both at the beginning and at the end of the treatment. Also, the weekly evolution of arterial blood pressure, proteinuria, and creatinine clearance was evaluated. Renal fibrosis was determined by Masson's trichrome staining. Interleukin (IL)-6, tumor necrosis factor (TNF)-α, and nuclear factor-κB (NF-κB) levels were determined by immunohistochemistry and confirmed by Western blotting analysis. The levels of glomerular nephrin were assessed by immunofluorescence. Chronic administration of ANG-(1-7) normalized arterial pressure, reduced glycemia and triglyceridemia, improved proteinuria, and ameliorated structural alterations in the kidney of SHRSP as shown by a restoration of glomerular nephrin levels as detected by immunofluorescence. These results were accompanied with a decrease in both the immunostaining and abundance of IL-6, TNF-α, and NF-κB. In this context, the current study provides strong evidence for a protective role of ANG-(1-7) in the kidney.

Topics: Angiotensin I; Animals; Blood Pressure; Interleukin-6; Kidney; Male; Membrane Proteins; NF-kappa B; Peptide Fragments; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium Chloride; Tumor Necrosis Factor-alpha

We assessed the contribution of angiotensin-(1-7) [Ang-(1-7)] to captopril-induced cardiovascular protection in spontaneously hypertensive rats (SHRs) chronically treated with the nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (SHR-l). NG-nitro-L-arginine methyl ester (80 mg/L) administration for 3 weeks increased mean arterial pressure (MAP) from 196 ± 6 to 229 ± 3 mm Hg (P < 0.05). Treatment of SHR-l with Ang-(1-7) antagonist [d-Ala7]-Ang-(1-7) (A779; 744 μg·kg(-1)·d(-1) ip) further elevated MAP to 253 ± 6 mm Hg (P < 0.05 vs SHR-l or SHR). Moreover, A779 treatment attenuated the reduction in MAP and proteinuria by either captopril (300 mg/L in drinking water) or hydralazine (1.5 mg·kg(-1)·d(-1) ip). In isolated perfused hearts, the recovery of left ventricular function from global ischemia was enhanced by captopril or hydralazine treatment and was exacerbated with A779. The Ang-(1-7) antagonist attenuated the beneficial effects of captopril and hydralazine on cardiac function. Recovery from global ischemia was also improved in isolated SHR-l hearts acutely perfused with captopril during both the perfusion and reperfusion periods. The acute administration of A779 reduced the beneficial actions of captopril to improve recovery after ischemia. We conclude that during periods of reduced nitric oxide availability, endogenous Ang-(1-7) plays a protective role in effectively buffering the increase in blood pressure and renal injury and the recovery from cardiac ischemia. Moreover, Ang-(1-7) contributes to the blood pressure lowering and tissue protective actions of captopril and hydralazine in a model of severe hypertension and end-organ damage.

Topics: Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Brain; Captopril; Cytokines; Heart; Hydralazine; Hypertension; In Vitro Techniques; Insulin; Kidney; Leptin; Male; Myocardial Contraction; Myocardial Reperfusion Injury; NG-Nitroarginine Methyl Ester; Peptide Fragments; Perfusion; Proteinuria; Rats; Rats, Inbred SHR; Ventricular Function, Left

Recent identification of a counterregulatory axis of the renin-angiotensin system, called angiotensin-converting enzyme 2-angiotensin-(1-7) [ANG-(1-7)]-Mas receptor, may offer new targets for the treatment of renal fibrosis. We hypothesized that therapy with ANG-(1-7) would improve glomerulosclerosis through counteracting ANG II in experimental glomerulonephritis. Disease was induced in rats with the monoclonal anti-Thy-1 antibody, OX-7. Based on a three-dose pilot study, 576 microg x kg(-1) x day(-1) ANG-(1-7) was continuously infused from day 1 using osmotic pumps. Measures of glomerulosclerosis include semiquantitative scoring of matrix proteins stained for periodic acid Schiff, collagen I, and fibronectin EDA+ (FN). ANG-(1-7) treatment reduced disease-induced increases in proteinuria by 75%, glomerular periodic acid Schiff staining by 48%, collagen I by 24%, and FN by 25%. The dramatic increases in transforming growth factor-beta1, plasminogen activator inhibitor-1, FN, and collagen I mRNAs seen in disease control animals compared with normal rats were all significantly reduced by ANG-(1-7) administration (P < 0.05). These observations support our hypothesis that ANG-(1-7) has therapeutic potential for reversing glomerulosclerosis. Several results suggest ANG-(1-7) acts by counteracting ANG II effects: 1) renin expression in ANG-(1-7)-treated rats was dramatically increased as it is with ANG II blockade therapy; and 2) in vitro data indicate that ANG II-induced increases in mesangial cell proliferation and plasminogen activator inhibitor-1 overexpression are inhibited by ANG-(1-7) via its binding to a specific receptor known as Mas.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Cell Proliferation; Cells, Cultured; Collagen Type I; Disease Models, Animal; Dose-Response Relationship, Drug; Fibronectins; Fibrosis; Gene Expression Regulation; Glomerulonephritis; Infusion Pumps, Implantable; Infusions, Subcutaneous; Isoantibodies; Kidney; Male; Mesangial Cells; Peptide Fragments; Peptidyl-Dipeptidase A; Plasminogen Activator Inhibitor 1; Proteinuria; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Time Factors; Transforming Growth Factor beta1

The mechanisms by which angiotensin-(1-7) [Ang-(1-7)] exerts its beneficial effects on end-organ damage associated with diabetes and hypertension are not well understood. The purpose of this study was A) to compare the effects of apocynin with Ang-(1-7) on renal vascular dysfunction and NADPH oxidase activity in a combined model of diabetes and hypertension and B) to further determine whether chronic treatment with Ang-(1-7) can modulate renal catalase, and peroxisome proliferator activated receptor- gamma (PPAR-gamma) levels in streptozotocin-induced diabetes in both normotensive Wistar Kyoto rats (WKY) and in spontaneously hypertensive rats (SHR). Apocynin or Ang-(1-7) treatment for one month starting at the onset of diabetes similarly attenuated elevation of renal NADPH oxidase activity in the diabetic SHR kidney and reduced the degree of proteinuria and hyperglycemia, but had little or modest effect on reducing mean arterial pressure. Both drugs also attenuated the diabetes-induced increase in renal vascular responsiveness to endothelin-1. Induction of diabetes in WKY and SHR animals resulted in significantly reduced renal catalase activity and in PPAR-gamma mRNA and protein levels. Treatment with Ang-(1-7) significantly prevented diabetes-induced reduction in catalase activity and the reduction in PPAR-gamma mRNA and protein levels in both animal models. Taken together, these data suggest that activation of Ang-(1-7)-mediated signaling could be an effective way to prevent the elevation of NADPH oxidase activity and inhibition of PPAR-gamma and catalase activities in diabetes and/or hypertension.

Topics: Acetophenones; Angiotensin I; Animals; Antihypertensive Agents; Antioxidants; Blood Glucose; Blood Pressure; Catalase; Diabetes Mellitus, Experimental; Endothelin-1; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Hyperglycemia; Hypertension; Kidney; Male; NADPH Oxidases; Peptide Fragments; PPAR gamma; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Artery

Exposure to clinically relevant doses of glucocorticoids during fetal life increases blood pressure in adult male and female sheep. The purpose of this study was to evaluate the effects of prenatal exposure to betamethasone at 80-81 days of gestation on renal function in ewes and rams at 1.5 yr of age. In prenatal betamethasone-exposed males, compared with the vehicle-exposed animals, basal glomerular filtration rate (GFR) (1.93 +/- 0.08 vs. 2.27 +/- 0.10 ml.min(-1).kg body wt(-1)) and the ability to excrete an acute Na+ load (37.1 +/- 4.4 vs. 53.7 +/- 9.7%) were reduced. (P < 0.03 and P = 0.03, respectively). In contrast, prenatal betamethasone exposure had no effect on basal GFR, Na+ excretion, or the percentage of the Na+ load excreted during the experiment in females. Systemic infusions of ANG-(1-7) at 9 ng.min(-1).kg(-1) for 2 h had minimal effects on basal GFR, renal plasma flow, and Na+ excretion in males but increased Na+ excretion in females. However, the percentage of Na+ load excreted during ANG-(1-7) infusion did not change in prenatal betamethasone-exposed females (113.1 +/- 14.2 vs. 98.1 +/- 12.2%) compared with the significant increase in vehicle females (139.2 +/- 22.3 vs. 92.2 +/- 7.5%) (P = 0.01). The data indicate that antenatal betamethasone exposure produces gender-specific alternations in renal function and thus suggest that different mechanisms underlie the antenatal steroid-induced elevations in blood pressure in male and female offspring.

Topics: Age Factors; Aging; Angiotensin I; Animals; Anti-Inflammatory Agents; Betamethasone; Blood Pressure; Creatinine; Female; Gestational Age; Glomerular Filtration Rate; Hypertension; Infusions, Intravenous; Kidney; Male; Natriuresis; Peptide Fragments; Potassium; Pregnancy; Prenatal Exposure Delayed Effects; Proteinuria; Renal Plasma Flow, Effective; Sex Factors; Sheep; Sodium

We examined the influence of chronic treatment with angiotensin-(1-7) [Ang-(1-7)] on renox (renal NADPH oxidase, NOX-4) and the development of renal dysfunction in streptozotocin-treated spontaneously hypertensive rats (diabetic SHR).. Mean arterial pressure, urinary protein and vascular responsiveness of the isolated renal artery to vasoactive agonists were studied in vehicle- or Ang-(1-7)-treated SHR and diabetic SHR.. Ang-(1-7) decreased the elevated levels of renal NADPH oxidase (NOX) activity and attenuated the activation of NOX-4 gene expression in the diabetic SHR kidney. Ang-(1-7) treatment increased sodium excretion but did not affect mean arterial pressure in diabetic SHR. There was a significant increase in urinary protein (266 +/- 22 mg/24 h) in the diabetic compared to control SHR (112 +/- 13 mg/24 h) and treatment of diabetic SHR with Ang-(1-7) reduced the degree of proteinuria (185 +/- 23 mg/24 h, p < 0.05). Ang-(1-7) treatment also attenuated the diabetes-induced increase in renal vascular responsiveness to endothelin-1, norepinephrine, and angiotensin II in SHR, but significantly increased the vasodilation of the renal artery of SHR and diabetic SHR to the vasodilator agonists.. These results suggest that treatment with Ang-(1-7) constitutes a potential therapeutic strategy to alleviate NOX-mediated oxidative stress and to reduce renal dysfunction in diabetic hypertensive rats.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme Activation; Gene Expression Regulation, Enzymologic; Hyperglycemia; Hypertension, Renal; Male; NADPH Oxidase 4; NADPH Oxidases; Peptide Fragments; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Vasoconstriction; Vasodilation

We recently demonstrated that renin-angiotensin system (RAS) overactivity during late gestation in rats is associated with increased kidney and urine levels of ANG-(1-7) and enhanced kidney immunostaining of ANG-(1-7) and angiotensin-converting enzyme 2 (ACE2). To understand the temporal-spatial changes in normal and hypertensive pregnancies, the renal distribution of ANG-(1-7) and ACE2 in association with kidney angiotensin peptides and ACE2 activity was examined in virgin, normal pregnant (NP; gestational days 5, 15, and 19) and reduced uterine perfusion pressure (RUPP at day 19) pregnant Sprague-Dawley rats. ANG-(1-7) and ACE2 immunocytochemical staining increased 1.8- and 1.9-fold and 1.7- and 1.8-fold, respectively, at days 15 and 19 of NP, compared with virgin rats. ANG-(1-7) and ANG II concentrations were increased in the kidney at 19 days of gestation. ACE2 activity measured using a fluorescent substrate was increased 1.9- and 1.9-fold in the cortex and 1.9- and 1.8-fold in the medulla at days 15 and 19 of NP. In the RUPP animals, ANG-(1-7) immunostaining and concentration were significantly decreased compared with 19-day NP rats. ACE2 activity was unchanged in the cortex and medulla of RUPP rats. In conclusion, during NP, the concurrent changes of ACE2 and ANG-(1-7) suggest that ACE2 plays an important role in regulating the renal levels of ANG-(1-7) at mid to late gestation. However, the decrease in renal ANG-(1-7) content in the absence of a concomitant decrease in ACE2 implicates the participation of other ANG-(1-7) forming or degrading enzymes during hypertensive pregnancy.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Blood Pressure; Body Weight; Estradiol; Female; Fluorescent Antibody Technique; Hypertension, Pregnancy-Induced; Immunohistochemistry; Kidney; Peptide Fragments; Peptidyl-Dipeptidase A; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Proteinuria; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Renin; Urodynamics; Uterus

For defining the pathogenic effects of the (pro)renin receptor-transgenic rat, strains that overexpressed the human receptor were generated. Although transgenic rats were normotensive and euglycemic and had a renal angiotensin II (AngII) level that was comparable to that of wild-type rats, transgenic rats developed proteinuria with aging and significant glomerulosclerosis at 28 wk of age. In kidneys of 28-wk-old transgenic rats, mitogen-activated protein kinases (MAPK) were activated without recognizable tyrosine phosphorylation of the EGF receptor, and expression of TGF-beta1 was enhanced. In vivo infusion of the (pro)renin receptor blocker peptide (formerly handle region decoy peptide) significantly inhibited the development of glomerulosclerosis, proteinuria, MAPK activation, and TGF-beta1 expression in the kidneys, but the angiotensin-converting enzyme inhibitor did not attenuate these changes despite a significant decrease in the renal AngII level. In addition, recombinant rat prorenin stimulated MAPK activation in the human receptor-expressed cultured cells, but human receptor was unable to evoke the enzyme activity of rat prorenin. Thus, human (pro)renin receptor elicits slowly progressive nephropathy by AngII-independent MAPK activation in rats. This study clearly provided in vivo evidence for the AngII-independent MAPK activation by human (pro)renin receptor and induction of glomerulosclerosis with increased TGF-beta1 expression.

Topics: Age Factors; Angiotensin I; Angiotensin II; Animals; Animals, Genetically Modified; Chlorocebus aethiops; COS Cells; Disease Progression; Glomerulosclerosis, Focal Segmental; Humans; MAP Kinase Signaling System; Prorenin Receptor; Proteinuria; Rats; Receptors, Cell Surface; Transforming Growth Factor beta1

Studies in experimental animals and younger women suggest a protective role for estrogen; however, clinical trials may not substantiate this effect in older females. Therefore, the present study assessed the outcome of ovariectomy in older mRen2. Lewis rats subjected to a high-salt diet for 4 wk. Intact or ovariectomized (OVX, 15 wk of age) mRen2. Lewis rats were aged to 60 wk and then placed on a high-salt (HS, 8% sodium chloride) diet for 4 wk. Systolic blood pressures were similar between groups [OVX 169 +/- 6 vs. Intact 182 +/- 7 mmHg; P = 0.22] after the 4-wk diet; however, proteinuria [OVX 0.8 +/- 0.2 vs. Intact 11.5 +/- 2.6 mg/mg creatinine; P < 0.002, n = 6], renal interstitial fibrosis, glomerular sclerosis, and tubular casts were lower in OVX vs. Intact rats. Kidney injury molecule-1 mRNA, a marker of tubular damage, was 53% lower in the OVX HS group. Independent from blood pressure, OVX HS rats exhibited significantly lower cardiac (24%) and renal (32%) hypertrophy as well as lower C-reactive protein (28%). Circulating insulin-like growth factor-I (IGF-I) levels were not different between the Intact and OVX groups; however, renal cortical IGF-I mRNA and protein were attenuated in OVX rats [P < 0.05, n = 6]. We conclude that ovariectomy in the older female mRen2. Lewis rat conveys protection against salt-dependent increase in renal injury.

Topics: Aging; Angiotensin I; Angiotensin II; Animals; Animals, Congenic; Blood Pressure; C-Reactive Protein; Cell Adhesion Molecules; Disease Models, Animal; Female; Fibrosis; Hypertension; Hypertrophy; Insulin-Like Growth Factor I; Intracellular Signaling Peptides and Proteins; Kidney; Kidney Diseases; Membrane Proteins; Ovariectomy; Peptide Fragments; Proteinuria; Rats; Rats, Inbred Lew; Renin; Renin-Angiotensin System; RNA, Messenger; Sodium Chloride, Dietary

We examined the influence of chronic treatment with ANG-(1-7) on development of hypertension and end-organ damage in spontaneously hypertensive rats (SHR) chronically treated with the nitric oxide synthesis inhibitor L-NAME (SHR-L-NAME). L-NAME administered orally (80 mg/l) for 4 wk significantly elevated mean arterial pressure (MAP) compared with SHR controls drinking regular water (269 +/- 10 vs. 196 +/- 6 mmHg). ANG-(1-7) (24 microg x kg(-1) x h(-1)) or captopril (300 mg/l) significantly attenuated the elevation in MAP due to L-NAME (213 +/- 7 and 228 +/- 8 mmHg, respectively), and ANG-(1-7) + captopril completely reversed the L-NAME-dependent increase in MAP (193 +/- 5 mmHg). L-NAME-induced increases in urinary protein were significantly lower in ANG-(1-7)-treated animals (226 +/- 6 vs. 145 +/- 12 mg/day). Captopril was more effective (96 +/- 12 mg/day), and there was no additional effect of captopril + ANG-(1-7) (87 +/- 5 mg/day). The abnormal vascular responsiveness to endothelin-1, carbachol, and sodium nitroprusside in perfused mesenteric vascular bed of SHR-L-NAME was improved by ANG-(1-7) or captopril, with no additive effect of ANG-(1-7) + captopril. In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischemia was significantly better in ANG-(1-7)- or captopril-treated SHR-L-NAME, with additive effects of combined treatment. The beneficial effects of ANG-(1-7) on MAP and cardiac function were inhibited when indomethacin was administered with ANG-(1-7), but indomethacin did not reverse the protective effects on proteinuria or vascular reactivity. The protective effects of the ANG-(1-7) analog AVE-0991 were qualitatively comparable to those of ANG-(1-7) but were not improved over those of captopril alone. Thus, during reduced nitric oxide availability, ANG-(1-7) attenuates development of severe hypertension and end-organ damage; prostaglandins participate in the MAP-lowering and cardioprotective effects of ANG-(1-7); and additive effects of captopril + ANG-(1-7) on MAP, but not proteinuria or endothelial function, suggest common, as well as different, mechanisms of action for the two treatments. Together, the results provide further evidence of a role for ANG-(1-7) in protective effects of angiotensin-converting enzyme inhibition and suggest dissociation of factors influencing MAP and those influencing end-organ damage.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Blood Pressure; Diuresis; Enzyme Inhibitors; Heart; Hypertension; Kidney; Male; Myocardial Ischemia; Myocardium; NG-Nitroarginine Methyl Ester; Peptide Fragments; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Recovery of Function; Reperfusion Injury; Severity of Illness Index; Vasomotor System

Intrarenal activation of the renin-angiotensin system has been suggested to play a pivotal role in the progression of various renal diseases, but the regulation of each component has not been fully clarified. We investigated the roles of nuclear factor kappaB (NF-kappaB) activation in the intrarenal renin-angiotensin system changes induced by proteinuria.. We used unilaterally nephrectomized rats loaded with bovine serum albumin as a model of proteinuric renal injury. Renal NF-kappaB activation was inhibited by gene transfer of the truncated form of IkappaBalpha via injection of a recombinant adenovirus vector into the renal artery, as we reported previously.. Inhibition of renal NF-kappaB activation attenuated the increases in intrarenal angiotensinogen protein (2.0-fold in rats with protein overloading and saline injection to 1.3-fold in rats with protein overloading and injection of a truncated form of IkappaBalpha) and angiotensin II (1.8-fold to 1.2-fold), and angiotensinogen mRNA. The increases in angiotensin-converting enzyme (ACE) and angiotensin II receptor type 2 were unaffected by NF-kappaB inhibition. The expression of ACE2, an enzyme that metabolizes angiotensins I and II, was decreased by 37%, and NF-kappaB inhibition abolished the decrease. Immunohistochemical analysis revealed that the angiotensinogen and ACE2 expression changes occurred mainly in proximal tubule cells (i.e., the target of adenoviral gene transfer).. These results indicate that proteinuria induces an increase in renal angiotensin II in an NF-kappaB-dependent manner. Induction of angiotensinogen and decrease in ACE2 levels may be involved in this NF-kappaB-dependent increase in angiotensin II.

Topics: Adenoviridae; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Carboxypeptidases; Dietary Proteins; Female; I-kappa B Proteins; Kidney; NF-kappa B; NF-KappaB Inhibitor alpha; Peptidyl-Dipeptidase A; Proteinuria; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; RNA, Messenger

Angiotensin-converting enzyme inhibitors (ACE-I) reduce proteinuria and protect the kidney in proteinuric renal disease. During ACE-I therapy, circulating levels of angiotensin (1-7) [Ang (1-7)] are increased. As cardiac and renal protective effects of Ang (1-7) have been reported, we questioned whether Ang (1-7) contributes to the anti-proteinuric effects of ACE-I treatment. Therefore, we evaluated whether Ang (1-7) infusion reduces proteinuria in a rat model of adriamycin-induced renal disease. In addition, the effect of a selective Ang (1-7) blocker, [D-Ala7]-Ang (1-7) (A779), was investigated in rats treated with the ACE-I, lisinopril (LIS). Six weeks after induction of proteinuria, therapy was started in four different groups: control, Ang (1-7), LIS, and LIS+A779. After two weeks, the rats were sacrificed. Six weeks after injection of adriamycin, the rats had developed proteinuria of 323+/-40 mg/24 hours. The proteinuria remained stable in the control group and in the Ang (1-7) group, but was reduced in both LIS and LIS+A779-treated groups. Similarly, blood pressure (BP) was unchanged in the control and the Ang (1-7) groups, but reduced in both the LIS and the LIS+A779 groups. Plasma levels of Ang (1-7) were increased in the Ang (1-7) and in both LIS-treated groups. We conclude that systemic Ang (1-7) plays no major role in the anti-proteinuric and BPlowering effects of ACE-I in this rat model of adriamycin-induced nephrosis.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Blood Pressure; Body Weight; Creatine; Creatinine; Doxorubicin; Male; Peptide Fragments; Peptidyl-Dipeptidase A; Proteinuria; Rats; Rats, Wistar

The systemic renin-angiotensin system (RAS) is suppressed in normal aging, but the activity of the tissue RAS is not well defined. We examined the systemic and intrarenal RAS status of aging normal rats and responses to suppression and stimulation of the production of endogenous ANG II. Studies were performed in young (3 mo) and early aging (15 mo) male Sprague-Dawley rats. Angiotensin-converting enzyme inhibitors modestly decreased mean arterial pressure (MAP) in young (3 mo) and early aging (15 mo) rats and limited proteinuria in the older rats. There were no significant age-related effects on renal function or on endogenous RAS activity. Intravenous infusion of the precursor ANG I led to comparable increases in MAP in younger and older rats. In contrast, the renal effects (reduction in glomerular filtration and plasma flow rates) were exaggerated in the older animals. Intrarenal arterial ANG I did not affect MAP in any group. In young rats, there were no significant hemodynamic effects in either the ipsilateral (infused) or the contralateral (noninfused) kidney. In the older rats, both kidneys had a significant fall in renal renal plasma flow rate (RPF) with left renal arterial infusion of ANG I. Accordingly, these studies early in the course of aging found only subtle changes in the activity, responsiveness, and metabolism of the RAS. Thus early aging is associated with a modest but important increase in sensitivity to RAS stimulation.

Topics: Aging; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Flow Velocity; Blood Pressure; Enalapril; Glomerular Filtration Rate; Infusions, Intra-Arterial; Infusions, Intravenous; Kidney; Male; Proteinuria; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

We evaluated the renal effects of the new angiotensin II type 1 (AT ) receptor antagonist, HR 720, in the stroke-prone spontaneously hypertensive rat. Rats were treated with either vehicle, HR 720, MK-954 (a selective AT1 receptor antagonist) or enalapril for 6 weeks. Blood pressure was decreased to a similar extent by HR 720, MK-954 and enalapril (203 +/- 4, 202 +/- 5 and 190 +/- 4 vs. 247 +/- 4 mm Hg for control). Urinary protein secretion was also decreased (5.2 +/- 0.3, 5.3 +/- 0.2 and 5.5 +/- 0.6 vs. 25.2 +/- 4.6 mg/100g/24h). The glomerular hypertensive change was improved in each drug-treated group (2.0 +/- 0.2, 3.3 +/- 0.3 and 1.6 +/- 0.1 vs. 17.6 +/- 1.5%; p < 0.0001). These results show that, in addition to its antihypertensive effect, HR 720 has a beneficial effect on renal function.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Blood Pressure; Body Weight; Cerebrovascular Disorders; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Imidazoles; Kidney; Kidney Function Tests; Kidney Glomerulus; Losartan; Organ Size; Proteinuria; Rats; Rats, Inbred SHR; Receptors, Angiotensin; Tetrazoles; Tissue Embedding

The pathophysiological role of angiotensin II in the development of renal sclerosis was investigated in 5/6-nephrectomized, 12-week-old male spontaneously hypertensive rats. After 1 week of a control period, nephrectomized rats received one of the following treatments for 4 weeks: the selective nonpeptide angiotensin II type 1 receptor antagonist TCV-116 (1 mg/kg per day), the angiotensin converting enzyme inhibitor delapril (30 mg/kg per day), hydralazine (15 mg/kg per day), or vehicle. Urinary protein and albumin excretions and systolic blood pressure were determined every week. Rats with reduced renal mass treated with vehicle had a poor survival rate (30%). Although TCV-116, delapril, and hydralazine treatment significantly improved the survival rate for 4 weeks, hydralazine failed to improve proteinuria and albuminuria as well as the decline in renal function compared with delapril or TCV-116. Histological examination revealed that both TCV-116 and delapril protected glomeruli from sclerosis, whereas hydralazine did not improve histological findings (5%, 7%, and 30% of glomeruli were affected, respectively). These results indicate that angiotensin II plays a dominant role through its type 1 receptor in the pathogenesis of renal deterioration by hypertension.

Topics: Albuminuria; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Chromatography, High Pressure Liquid; Hydralazine; Hypertension; Indans; Kidney; Male; Proteinuria; Rats; Rats, Inbred SHR; Survival Analysis; Tetrazoles

The effects of the angiotensin converting enzyme (ACE) inhibitor enalapril on the proteinuria and degree of focal glomerular sclerosis hyalinosis (FSH) in chronic puromycin aminonucleoside nephropathy (PAN) were examined. Chronic PAN was induced in male Sprague-Dawley rats by seven subcutaneous injections of puromycin aminonucleoside (20 mg/kg) over 10 weeks (Groups I and II). Group II rats also received enalapril 10 mg/kg/day in the drinking water throughout the study (12 weeks). Group III rats served as age-matched controls. Proteinuria was similar in Groups I and II (35.5 +/- 9.7 versus 29.1 +/- 4.1 mg protein/mg creatinine, mean +/- SEM, P greater than 0.05). Serum creatinine remained unchanged in Group I, but rose from 0.7 +/- 0.04 to 1.2 +/- 0.1 mg/dl (mean +/- SEM, P less than 0.05) in Group II. FSH was 13.8% in Group I, 12.9% in Group II (P greater than 0.05), and 0.6% in Group III. There was no significant difference in glomerular lipid content and in immunofluorescence for rat albumin, fibrinogen, IgM, IgG, and C3 between Groups I and II. ACE activity was inhibited by 94% in serum, 83% in lungs, and 92% in kidneys; and blood pressure response to. Angiotensin I challenge was decreased by 50% in rats similarly treated with enalapril versus controls. In summary, proteinuria and glomerular sclerosis in this model are not affected by ACE inhibition.

Topics: Angiotensin I; Animals; Blood Pressure; Creatinine; Enalapril; Kidney; Lung; Male; Peptidyl-Dipeptidase A; Proteinuria; Puromycin; Puromycin Aminonucleoside; Rats; Rats, Inbred Strains