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
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.