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bioRxiv · 10.1101/303768

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

Zou, H.-h.·Wang, L.·Shen, Y.·Zheng, X.·Xu, G.
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Abstract

ETBR 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.

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Zou, H.-h., Wang, L., Shen, Y., Zheng, X., Xu, G.. 2018-04-18. Endothelial cells secreted ET-1 augments DN via inducing EM accumulation of MCs in ETBR-/- mice. https://doi.org/10.1101/303768

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