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Angiotensin(1-7) attenuates the progression of streptozotocin-induced diabetic renal injury better than angiotensin receptor blockade.

ABSTRACT: To explore the potential therapeutic effects of angiotensin(1-7) (Ang(1-7)), an endogenous ligand of the Mas receptor, on streptozotocin-induced diabetic nephropathy, male Wistar rats were randomly divided into two groups: a control group and a diabetic model group. After 12 weeks, the diabetic rats were divided into subgroups for 4-week treatments consisting of no-treatment group, small-, moderate-, and large-dose Ang(1-7) groups, a valsartan group, a large-dose Ang(1-7) plus valsartan group, and an A779 (antagonist of the Mas receptor) group, each with 15 rats. Ang(1-7) improved renal function, attenuated glomeruli sclerosis, oxidative stress, and cell proliferation, decreased the expression of collagen IV, TGF-?1, VEGF, NOX4, p47phox, PKC?, and PKC?1, and the phosphorylation of Smad3. In the rat mesangial HBZY-1 cell line, Ang(1-7) decreased high-glucose-induced oxidative stress, the proliferation and expression of NOX4, p47phox, and TGF-?1, the phosphorylation of Smad3, collagen IV, and VEGF, and the membrane translocation of PKC? and PKC?1. A779 blocked the effects of Ang(1-7) both in vivo and in vitro. The effects of large-dose Ang(1-7) alone and in combination with valsartan were superior to valsartan alone, but the combination had no significant synergistic effect compared with Ang(1-7) alone. Thus, Ang(1-7) ameliorated streptozotocin-induced diabetic renal injury. Large-dose treatment was superior to valsartan in reducing oxidative stress and inhibiting TGF?1/Smad3- and VEGF-mediated pathways.

SUBMITTER: Zhang K

PROVIDER: S-EPMC4317508 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Angiotensin(1-7) attenuates the progression of streptozotocin-induced diabetic renal injury better than angiotensin receptor blockade.

Zhang Kai K Meng Xiao X Li Dongmei D Yang Jianmin J Kong Jing J Hao Panpan P Guo Tao T Zhang Meng M Zhang Yun Y Zhang Cheng C

Kidney international 20140730 2

To explore the potential therapeutic effects of angiotensin(1-7) (Ang(1-7)), an endogenous ligand of the Mas receptor, on streptozotocin-induced diabetic nephropathy, male Wistar rats were randomly divided into two groups: a control group and a diabetic model group. After 12 weeks, the diabetic rats were divided into subgroups for 4-week treatments consisting of no-treatment group, small-, moderate-, and large-dose Ang(1-7) groups, a valsartan group, a large-dose Ang(1-7) plus valsartan group, a ...[more]

PMID: 25075768

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Project description:Both angiotensin II type 1 receptor (AT1R) and nuclear factor-kappa B (NF-?B) play significant roles in the pathogenesis of hypertension and type 2 diabetes. However, the role of NF-?B in perpetuating renal AT1 receptors dysfunction remains unclear. The aim of the present study to determine whether blockade of NF-?B, could reverse the exaggerated renal AT1R function, reduce inflammatory state and oxidative stress, lower blood pressure in Zucker diabetic fatty (ZDF) rats.Pyrrolidine dithiocarbamate (PDTC), a NF-?B inhibitor (150 mg/kg in drinking water)or vehicle was administered orally to 12-weeks-old ZDF rats and their respective control lean Zucker (LZ) rats for 4 weeks. Blood pressure was measured weekly by tail-cuff method. AT1R functions were determined by measuring diuretic and natriuretic responses to AT1R antagonist (candesartan; 10 ?g/kg/min iv). The mRNA and protein levels of NF-?B, oxidative stress maker and AT1R were determined using quantitative real-time PCR and Western blotting, respectively. The NF-?B-DNA binding activity in renal cortex was measured by Electrophoretic mobility shift assay (EMSA).As compared with LZ rats, ZDF rats had higher blood pressure, impaired natriuresis and diuresis, accompanied with higher levels of oxidative stress and inflammation. Furthermore, AT1R expression was higher in renal cortex from ZDF rats; candesartan induced natriresis and diuresis, which was augmented in ZDF rats. Treatment with PDTC lowered blood pressure and improved diuretic and natriuretic effects in ZDF rats; meanwhile, the increased oxidative stress and inflammation were reduced; the increased AT1R expression and augmented candesartan-mediated natriuresis and diuresis were recoverd in ZDF rats. Our further study investigated the mechanisms of PDTC on AT1R receptor expression. It resulted that PDTC inhibited NF-?B translocation from cytosol to nucleus, inhibited binding of NF-?B with AT1R promoter, therefore, reduced AT1R expression and function.Our present study indicates blockade of NF-?B, via inhibition of binding of NF-?B with AT1R promoter, reduces renal AT1R expression and function, improves oxidative stress and inflammatory/anti-inflammatory balance, therefore, lowers blood pressure and recovers renal function in ZDF rats.

Project description:BackgroundDiabetic nephropathy (DN) is a severe complication of diabetes mellitus (DM). Pancreas or islet transplantation has been reported to prevent the development of DN lesions and ameliorate or reverse existing glomerular lesions in animal models. Shortage of pancreas donor is a severe problem. Islets derived from stem cells may offer a potential solution to this problem.ObjectiveTo evaluate the effect of stem cell-derived islet transplantation on DN in a rat model of streptozotocin-induced DM.MethodsPancreatic progenitor cells were isolated from aborted fetuses of 8 weeks of gestation. And islets were prepared by suspension culture after a differentiation of progenitor cells in medium containing glucagon-like peptide-1 (Glp-1) and nicotinamide. Then islets were transplanted into the liver of diabetic rats via portal vein. Blood glucose, urinary volume, 24 h urinary protein and urinary albumin were measured once biweekly for 16 weeks. Graft survival was evaluated by monitoring human C-peptide level in rat sera and by immunohistochemical staining for human mitochondrial antigen and human C-peptide in liver tissue. The effect of progenitor-derived islets on filtration membrane was examined by electron microscopy and real-time polymerase chain reaction (PCR). Immunohistochemical staining, real-time PCR and western blot were employed for detecting fibronectin, protein kinase C beta (PKCβ), protein kinase A (PKA), inducible nitric oxide synthase (iNOS) and superoxide dismutase (SOD).ResultsIslet-like clusters derived from 8th gestational-week human fetal pancreatic progenitors survived in rat liver. And elevated serum level of human C-peptide was detected. Blood glucose, 24 h urinary protein and urinary albumin were lower in progenitor cell group than those in DN or insulin treatment group. Glomerular basement membrane thickness and fibronectin accumulation decreased significantly while podocytes improved morphologically in progenitor cell group. Furthermore, receptor of advanced glycation end products and PKCβ became down-regulated whereas PKA up-regulated by progenitor cell-derived islets. And iNOS rose while SOD declined.ConclusionsDN may be reversed by transplantation of human fetal pancreatic progenitor cell-derived islets. And fetal pancreatic progenitor cells offer potential resources for cell replacement therapy.

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Angiotensin(1-7) attenuates the progression of streptozotocin-induced diabetic renal injury better than angiotensin receptor blockade.

Publications

Angiotensin(1-7) attenuates the progression of streptozotocin-induced diabetic renal injury better than angiotensin receptor blockade.

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