Endothelial cells secreted endothelin-1 augments diabetic nephropathy via inducing extracellular matrix accumulation of mesangial cells in ETBR -/- mice

• Published in: Aging (Albany, NY.) NY.), 2019-03, Vol.11 (6), p.1804-1820
• Main Authors: Zou, Hong-Hong, Wang, Li, Zheng, Xiao-Xu, Xu, Gao-Si, Shen, Yunfeng
• Format: Article
• Language: English
• Subjects: Animals; Diabetic Nephropathies - metabolism; Endothelin-1 - metabolism; Extracellular Matrix - metabolism; Mesangial Cells - metabolism; Mice; Receptor, Endothelin B - deficiency; Research Paper; Up-Regulation - genetics
• ISSN: 1945-4589; 1945-4589
• DOI: 10.18632/aging.101875

Endothelin B receptor (ETBR) deficiency may contribute to the progression of diabetic nephropathy (DN) in a streptozotocin (STZ) model, but the underlying mechanism is not fully revealed. In this study, STZ-diabetic ETBR mice was characterized by increased serum creatinine and urinary albumin, enhanced glomerulosclerosis, and upregulated ET-1 expression compared with STZ-diabetic WT mice. , HG conditioned media (CM) of ETBR GENs promoted mesangial cell proliferation and upregulated ECM-related proteins, and ET-1 knockout in GENs or inhibition of ET-1/ETAR in mesangial cell suppressed mesangial cell proliferation and collagen IV formation. In addition, ET-1 was over-expressed in ETBR GENs and was regulated by NF-kapapB pathway. ET-1/ETBR suppressed NF-kappaB to modulate ET-1 in GENs. Furthermore, ET-1/ETAR promoted RhoA/ROCK pathway in mesangial cells, and accelerated mesangial cell proliferation and ECM accumulation. Finally, experiments proved inhibition of NF-kappaB pathway ameliorated DN in ETBR mice. These results suggest that in HG-exposed ETBR GENs, suppression of ET-1 binding to ETBR activated NF-kappaB pathway, thus to secrete large amount of ET-1. Due to the communication between GENs and mesangial cells in diabetes, ET-1 binding to ETAR in mesangial cell promoted RhoA/ROCK pathway, thus to accelerate mesangial cell proliferation and ECM accumulation.