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.
Highlights
Diabetic nephropathy (DN), characterized by renal inflammation, urinary albumin, decreased glomerular filtration rate, glomerulosclerosis and tubulointerstitial fibrosis, is a leading cause of end-stage renal disease (ESRD) [1,2]
Periodic acid‐Schiff (PAS) staining showed that enlargement of glomeruli was observed in STZ-diabetic mice, and enhanced glomerulosclerosis was present in STZ-diabetic Endothelin B receptor (ETBR)-/- mice, which was validated by glomerulosclerosis index (Figure 2C)
We observed that STZ-diabetic ETBR-/- mice had higher levels of renal damage signs, increased mRNA and protein levels of ET-1, enhanced glomerulosclerosis, and increased collagen in the glomeruli in vivo
Summary
Diabetic nephropathy (DN), characterized by renal inflammation, urinary albumin, decreased glomerular filtration rate, glomerulosclerosis and tubulointerstitial fibrosis, is a leading cause of end-stage renal disease (ESRD) [1,2]. Mesangial cells (MC) are critical in maintaining mesangial matrix homeostasis, regulating glomerular filtration rate, and keeping normal glomerular function via producing cytokines, metalloproteinases and extracellular matrix (ECM) [3]. Researchers have found that mesangial cell proliferation and ECM accumulation were main contributing factors to glomerulosclerosis and tubulointerstitial fibrosis, which were important characters of DN [4,5]. In highglucose (HG) condition, fibronectin, collagen IV, and www.aging‐us.com plasminogen activator inhibitor were observed to be upregulated in mesangial cells [6]. Connective tissue growth factor (CTGF), a growth factor produced by activated mesangial cells, played a key role in the pathogenesis of DN and was upregulated in DN [7]. Glomerulosclerosis is closely associated with dysfunction of mesangial cells under HG condition
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