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


METHODS
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.


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.


CONCLUSIONS
Our results strongly suggest that urocortin 1 improved renal function in rats with DN by inhibiting the overproduction of TGF-beta1 and VEGF.
Li
Xuan
X
Department of Pharmacology, Nanjing Medical University, Nanjing 210029, China.
Hu
Jue
J
Zhang
Qichun
Q
Sun
Xiaoyu
X
Li
Shengnan
S
D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D054832:Urocortins / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*
D053773:Transforming Growth Factor beta1; D054832:Urocortins; D042461:Vascular Endothelial Growth Factor A