Urotensin II inhibits autophagy in renal tubular epithelial cells and induces ECM production in early diabetic mice.

Aim/Introduction Urotensin II (UII) and autophagy have been considered as important components in the pathogenesis of diabetic nephropathy. The present study explores whether UII can regulate autophagy in kidney and its effect in diabetes. Materials and Methods Immunohistochemistry and western blot were conducted on the kidney tissues of diabetic UII receptor (UT) gene knock-out mice, wild type diabetic mice, and normal control mice. For in vitro experiment, HK-2 cells were treated with UII (10-7 mol/L) in the presence or absence of UT antagonist, SB-657510, (10-6 mol/L) or autophagy inducer Rapamycin (10-3 mol/L) for 12 h. Markers for autophagy (LC3-II, p62/SQSTM1) and extracellular matrix (fibronectin, collagen IV) were analyzed. Results In diabetic UT knock-out mice, expression of LC3-II is increased and p62 is reduced in comparison to that of the normal diabetic mice. Fibronectin and collagen IV are down-regulated in diabetic UT knock-out mice when compared to that of the normal diabetic mice. For in vitro cell experiment, UII is shown to inhibit expression LC3-II and increase expression of p62 in comparison to that of the normal control. Treatment with SB-657510 can block UII-induced down-regulation of LC3-II and upregulation of p62 while inhibiting UII-induced upregulation of fibronectin and collagen IV. Adding autophagy inducer Rapamycin also inhibited UII-induced upregulation of fibronectin and collagen IV. Conclusion Our study is the first to show that UII can down-regulate autophagy in kidney while accompanying the increased production of ECM in early diabetes. Our in vitro study also demonstrates that upregulation of autophagy can decrease UII-induced production of ECM in HK-2 cell. This article is protected by copyright. All rights reserved.