Endothelial cells secreted ET-1 augments DN via inducing EM accumulation of MCs in ETBR−/− mice

Abstract

AbstractETBR deficiency may contribute to the progression of DN in a STZ model, but the underlying mechanism is not fully revealed. In this study, STZ-diabetic ETBR−/− mice was characterized by increased serum creatinine, urinary albumin and ET-1 expression, and enhanced glomerulosclerosis compared with STZ-diabetic WT mice. HG conditioned media of ETBR−/− endothelial cells promoted MC proliferation and upregulated ECM-related proteins, and ET-1 knockout in endothelial cells or inhibition of ET-1/ETAR in MC suppressed MC proliferation. ET-1 was over-expressed in ETBR−/− endothelial cells and was regulated by NF-kapapB pathway. And ET-1/ETBR suppressed NF-kappaB via eNOS to modulate ET-1 in endothelial cells. Furthermore, ET-1/ETAR promoted RhoA/ROCK pathway in MC, and accelerated MC proliferation and ECM accumulation. In vivo experiments proved ETBR−/− mice inhibited NF-kappaB pathway to ameliorate DN and eNOS mice had similar results. Hence, in HG-exposed ETBR−/− endothelial cells, suppression of ET-1/ETBR activated NF-kappaB pathway via inhibiting eNOS to secrete large amount of ET-1. Due to the communication between endothelial cells and MCs, ET-1/ETAR in MC promoted RhoA/ROCK pathway to accelerate MC proliferation and ECM accumulation.