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Urocortin 1 improves renal function in rats with streptozotocin-induced diabetes by inhibiting overproduction of TGF-beta 1 and VEGF.

ABSTRACT: BACKGROUND AND PURPOSE: Renal function can be assessed by measuring albuminuria and glomerular filtration rate, and the latter is often estimated by creatinine clearance rate (Ccr). Transforming growth factor-beta1 (TGF-beta1) and vascular endothelial growth factor (VEGF) are two important factors involved in the progressive loss of renal function in diabetic nephropathy (DN), especially in terms of albuminuria. We investigated the effect of urocortin 1 on renal function of rats with DN and the mechanisms involved. EXPERIMENTAL APPROACH: A modified rat model of DN (multiple injections of low-dose streptozotocin and complete Freund's adjuvant) and a rat mesangial cell line were used. Albuminuria and Ccr were measured or calculated. Expression and secretion of TGF-beta1 and VEGF were measured by immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) or enzyme-linked immunosorbent assay (R&D System, Inc., Minneapolis, MA, USA). Urocortin 1 and astressin [a non-selective antagonist of corticotrophin-releasing factor (CRF) receptors] were given as daily injections for 8 weeks. KEY RESULTS: Treatment of DN rats with urocortin 1 decreased albuminuria, renal weight and overexpression of TGF-beta1 and VEGF but enhanced Ccr. Furthermore, VEGF mRNA was increased in kidneys of DN rats, and this increase was reduced by treatment with urocortin 1. The secretion of VEGF induced by TGF-beta1 in mesangial cells was inhibited by urocortin 1 pretreatment. Astressin given with urocortin 1 prevented most of the effects of urocortin 1, in our models, in vivo or in vitro. CONCLUSION AND IMPLICATIONS: Our results strongly suggest that urocortin 1 improved renal function in rats with DN by inhibiting the overproduction of TGF-beta1 and VEGF.

SUBMITTER: Li X

PROVIDER: S-EPMC2737658 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Urocortin 1 improves renal function in rats with streptozotocin-induced diabetes by inhibiting overproduction of TGF-beta 1 and VEGF.

Li Xuan X Hu Jue J Zhang Qichun Q Sun Xiaoyu X Li Shengnan S

British journal of pharmacology 20090518 6

<h4>Background and purpose</h4>Renal function can be assessed by measuring albuminuria and glomerular filtration rate, and the latter is often estimated by creatinine clearance rate (Ccr). Transforming growth factor-beta1 (TGF-beta1) and vascular endothelial growth factor (VEGF) are two important factors involved in the progressive loss of renal function in diabetic nephropathy (DN), especially in terms of albuminuria. We investigated the effect of urocortin 1 on renal function of rats with DN a ...[more]

PMID: 19466989

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Project description:Diabetic nephropathy (DN) is one of the main causes of renal fibrosis and is associated with high morbidity and mortality. Traditional Chinese Medicine (TCM) therapy has a long history of usage in a clinical setting and its usage is increasing. ErHuang Formula (EHF), a Chinese herbal compound, has been clinically used in treating DN for more than 30 years. However, its mechanism of action is still unknown. This study was conducted to evaluate the effect of EHF on renal fibrosis in a DN rat model and explore its underlying mechanism. The DN rat model was established by high-sugar-fat diet combined with a single intraperitoneal injection of streptozotocin (STZ), and EFH extract (4, 2, 1 g/kg d-1) was administered orally for 8 weeks. The biochemical parameters (blood glucose, weight, Scr, BUN, UA, U-Alb and UAE) were analyzed. The pathological changes in renal tissue were observed by histological staining with H&E and Masson. The effect of EHF on the proliferation of NRK-49F cells was examined by CCK-8 assay and the levels of several inflammation and fibrosis related cytokines (IL-6, TNF-α, TGF-β1, Collagen I/III, MMP2/9) in serum and NRK-49F cell culture supernatants were detected by enzyme-linked immunoassay (ELISA). The mRNA levels of CXCL6, CXCR1, Collagen I/III, MMP2/9 in renal tissue were also measured by quantitative RT-PCR. Furthermore, the protein expression of PCNA, Collagen I/III, MMP2/9, CXCL6, CXCR1, p-STAT3, STAT3 in renal tissue and NRK-49F cells were determined by western blot. EHF improved the abnormal biochemical parameters and ameliorated the abnormal histology and fibrosis of renal tissue in a dose-dependent manner. EHF inhibited NRK-49F proliferation and decreased the expressions of inflammation and fibrosis related factors both in vitro and in vivo. Interestingly, the levels of Collagen I/III, PCNA, MMP2/9 and p-STAT3 were positively correlated with CXCL6. The amelioration of renal fibrosis in DN by EHF is related to CXCL6/JAK/STAT3 signal pathway, which is associated with inflammation and fibrosis of the tissue. These findings may have clinical implications for the treatment of DN.

Dataset Information

Urocortin 1 improves renal function in rats with streptozotocin-induced diabetes by inhibiting overproduction of TGF-beta 1 and VEGF.

Publications

Urocortin 1 improves renal function in rats with streptozotocin-induced diabetes by inhibiting overproduction of TGF-beta 1 and VEGF.

Similar Datasets

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