Urocortin ameliorates diabetic nephropathy in obese db/db mice.
OBJECTIVE
Hyperglycaemia induces overproduction of mitochondrial reactive oxygen species (ROS) in endothelial cells, which is believed to be a major molecular mechanism underlying complications of diabetes, including diabetic nephropathy. Impairment of endothelium-dependent vasodilatation is found in type 2 diabetes. Urocortin is a 40 amino-acid peptide related to the corticotrophin-releasing factor (CRF) family, which suppresses production of ROS in endothelial cells and sustains endothelium-dependent relaxations of rat coronary artery. However, it is not clear if urocortin has any effect on diabetic nephropathy.


METHODS
Possible mechanisms underlying the effects of urocortin on diabetic nephropathy were investigated in db/db mice and cultured rat mesangial cells.


RESULTS
Urocortin decreased body weight, plasma levels of advanced glycation end-products, blood urea nitrogen and creatinine levels. However, food intake, plasma insulin and glucose levels remained unaffected. Superoxide dismutase activity was increased markedly, whereas malonaldehyde levels in kidney homogenate and sorbitol concentrations in red blood cells were decreased significantly in urocortin-treated mice. Urocortin significantly decreased glomerular extracellular matrix expansion and accumulation in kidney. Moreover, urocortin inhibited the overexpression of transforming growth factor-beta 1 and connective tissue growth factor in rat mesangial cells induced by 25 mM glucose. All the effects of urocortin, except sorbitol accumulation, were abolished by the non-selective CRF receptor blocker, astressin.


CONCLUSIONS
Urocortin could significantly ameliorate diabetic nephropathy and this effect was mediated via the CRF receptor.
Li
X
X
Department of Pharmacology, Nanjing Medical University, Nanjing, PR China.
Hu
J
J
Zhang
R
R
Sun
X
X
Zhang
Q
Q
Guan
X
X
Chen
J
J
Zhu
Q
Q
Li
S
S
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001806:Blood Urea Nitrogen; D001835:Body Weight; D002460:Cell Line; D055513:Connective Tissue Growth Factor; D003404:Creatinine / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004435:Eating; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D017127:Glycation End Products, Advanced / Q000097:blood; D017874:Immediate-Early Proteins / Q000378:metabolism; D007328:Insulin / Q000097:blood; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009765:Obesity / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D013012:Sorbitol / Q000097:blood; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D054832:Urocortins / Q000378:metabolism*
D001786:Blood Glucose; C526318:CCN2 protein, mouse; C526316:CCN2 protein, rat; D017127:Glycation End Products, Advanced; D017874:Immediate-Early Proteins; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D018019:Receptors, Corticotropin-Releasing Hormone; D053773:Transforming Growth Factor beta1; D054832:Urocortins; D055513:Connective Tissue Growth Factor; D008315:Malondialdehyde; D013012:Sorbitol; D003404:Creatinine; D013482:Superoxide Dismutase