Research Paper Volume 11, Issue 6 pp 1804—1820
Endothelial cells secreted endothelin-1 augments diabetic nephropathy via inducing extracellular matrix accumulation of mesangial cells in ETBR-/- mice
- 1 Department of Nephrology, the Second Affiliated Hospital of Nanchang University, Nanchang, China
- 2 Division of Renal Diseases and Hypertension, Department of Medicine, The George Washington University, Washington, DC 20052, USA
- 3 Department of Endocrinology, the Second Affiliated Hospital of Nanchang University, Nanchang, China
received: January 17, 2019 ; accepted: March 10, 2019 ; published: March 29, 2019 ;
https://doi.org/10.18632/aging.101875How to Cite
Copyright: Zou et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
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. In vitro, 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, in vivo 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.