Abstract
Tubulointerstitial fibrosis is both a pathological manifestation of chronic kidney disease and a driving force for the progression of kidney disease. A previous study has shown that bone morphogenetic protein-binding endothelial cell precursor-derived regulator (BMPER) is involved in lung fibrogenesis. However, the role of BMPER in renal fibrosis remains unknown. In the present study, the expression of BMPER was examined by real-time PCR, Western blot and immunohistochemical staining. The in vitro effects of BMPER on tubular dedifferentiation and fibroblast activation were analyzed in cultured HK-2 and NRK-49F cells. The in vivo effects of BMPER were dissected in unilateral ureteral obstruction (UUO) mice by delivery of BMPER gene via systemic administration of plasmid vector. We reported that the expression of BMPER decreased in the kidneys of UUO mice and HK-2 cells. TGF-β1 increased inhibitor of differentiation-1 (Id-1) and induced epithelial mesenchymal transition in HK-2 cells, and knockdown of BMPER aggravated Id-1 up-regulation, E-cadherin loss, and tubular dedifferentiation. On the contrary, exogenous BMPER inhibited Id-1 up-regulation, prevented E-cadherin loss and tubular dedifferentiation after TGF-β1 exposure. In addition, exogenous BMPER suppressed fibroblast activation by hindering Erk1/2 phosphorylation. Knockdown of low-density lipoprotein receptor-related protein 1 abolished the inhibitory effect of BMPER on Erk1/2 phosphorylation and fibroblast activation. Moreover, delivery of BMPER gene improved renal tubular damage and interstitial fibrosis in UUO mice. Therefore, BMPER inhibits TGF-β1-induced tubular dedifferentiation and fibroblast activation and may hold therapeutic potential for tubulointerstitial fibrosis.
Highlights
Chronic kidney disease (CKD), unlike acute kidney injury, is manifested by a gradual decline in kidney function
By using in vivo unilateral ureteral obstruction (UUO) and in vitro TGF-β1-induced renal fibrosis model, we found that bone morphogenetic protein-binding endothelial cell precursor-derived regulator (BMPER) regulated both tubular dedifferentiation and fibroblast activation, thereby affecting the process of renal fibrosis
To assess whether BMPER is involved in Epithelial mesenchymal transition (EMT) mediated by TGF-β1, we examined the Ecadherin and α-smooth muscle actin (α-SMA) levels after BMPER down-regulation with siRNA knockdown in HK-2 cells
Summary
Chronic kidney disease (CKD), unlike acute kidney injury, is manifested by a gradual decline in kidney function. The shared feature of CKD is tubulointerstitial fibrosis and glomerulosclerosis in tubular and glomerulus compartments (Ruiz-Ortega et al, 2020). Studies have shown that, compared with glomerulosclerosis, the degree of tubulointerstitial fibrosis can better reflect the impaired renal function (Boor and Floege, 2012). Tubulointerstitial fibrosis is a pathological appearance of CKD, and. BMPER Ameliorates Renal Fibrosis a driving force for the kidney disease progression (Herrera et al, 2018). Strategies for ameliorating renal interstitial fibrosis could blunt kidney disease progression and improve kidney function. A variety of molecules have been found to regulate renal fibrosis in basic research, they have not been clinically used. It is imperative to develop more effective treatment approaches for renal fibrosis
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