Melatonin Attenuates Endothelial-to-Mesenchymal Transition of Glomerular Endothelial Cells via Regulating miR-497/ROCK in Diabetic Nephropathy

Abstract

Background/Aims: Endothelial-to-mesenchymal transition (EndMT) of glomerular endothelial cells (GEnCs) can induce albuminuria in diabetic nephropathy. Melatonin attenuates diabetic nephropathy, but its role and mechanism in EndMT of GEnCs in diabetic nephropathy remain unknown. Methods: The effect of melatonin on EndMT induced by transforming growth factor (TGF)-β2 in human renal GEnCs was determined by assaying the expression of endothelial marker cells (VE-cadherin and CD31) and mesenchymal cells (α-SMA and Snail), as well as monolayer permeability. The molecular mechanism of melatonin in these processes was focused on miR-497/ROCK signaling. Furthermore, the effect and mechanism of melatonin in EndMT were confirmed in glomeruli of rats with streptozotocin-induced diabetes. Results: Melatonin increased expression of VE-cadherin and CD31 and inhibited α-SMA and Snail levels that were altered by TGF-β2 in GEnCs. Melatonin treatment reduced expression and activity of ROCK1 and ROCK2, which suppressed TGF-β2-induced hyperpermeability of GEnCs and EndMT of GEnCs. Melatonin reduced ROCK1 and ROCK2 expression and activity in TGF-β2-stimulated GEnCs by enhancing expression of miR-497, which targets ROCK1 and ROCK2. Furthermore, we found that melatonin inhibited EndMT in glomeruli and albuminuria in rats with streptozotocin-induced diabetes. MiR-497 expression increased, whereas ROCK1 and ROCK2 expression and activity decreased in melatonin-treated diabetic rats. Conclusion: Melatonin attenuated EndMT of GEnCs via regulating miR-497/ROCK signaling in diabetic nephropathy. This study improves understanding of EndMT and the role of melatonin in diabetic nephropathy.

Melatonin: new insights on its therapeutic properties in diabetic complications

“…Aberrant angiogenesis has a pathological role in diabetic nephropathy; however, endothelial-to-mesenchymal transition of glomerular endothelial cells results in enhanced permeability, leading to proteinuria [177,178]. Melatonin inhibits endothelial-to-mesenchymal transition (EMT) in glomerular endothelial cells exposed to transforming growth factor-β2 (TGF-β2) and in the glomeruli of diabetic rats; this effect is mediated by the up-regulation of miR-497 expression leading to inhibited RhoA/Rho kinase (ROCK) activity [179].…”

Non-Coding RNAs in IGF-1R Signaling Regulation: The Underlying Pathophysiological Link between Diabetes and Cancer

“…This means that the same miRNAs may play distinct functions based on the stages of the disease or different tissues affected. For instance, apart from the pancreas, in the kidney, miR-497 shows a protective role in attenuating the deterioration of diabetic nephropathy by decreasing proteinuria as a downstream effector of TGF-β [63].…”

Disturbances in angiogenesis and vascular maturation in the skin are associated with diabetic kidney disease in type 1 diabetes

“…According to previous studies, endothelial-to-mesenchymal transition is associated with albuminuria in diabetic nephropathy. In these studies, a decreased number of CD31+ endothelial cells and increased a-SMA expression in glomeruli of diabetic mice was observed [21,22].…”

“…The study group consisted of 148 (87 men) consecutive patients with type 1 diabetes, median age (IQR) of 41 (31-49) years and diabetes duration of 21 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) years. The patients were under the care of the Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences.…”