Hypoxia inducible factor‐1α mediates the profibrotic action of albumin in renal tubular cells (690.12)

Abstract

Proteinuria is closely associated with the progression of chronic kidney diseases (CKD) by producing renal tubulointerstitial fibrosis. Over‐activation of hypoxia inducible factor (HIF)‐1α has also been implicated in the progression of CKD. The present study tested whether HIF‐1α mediated albumin‐induced profibrotic action in cultured rat renal proximal tubular cells. Western blot assay showed that incubation of the cells with albumin (20 μg/ml) for 48 hrs significantly increased HIF‐1α protein level by 2.26 ± 0.33 fold, collagen‐I by 2.13 ± 0.037 fold and tissue inhibitor of metalloproteinase (TIMP)‐1 by 1.99 ± 0.12 fold, respectively. HIF‐1α shRNA blocked albumin‐induced increases in collagen‐I (0.54 ± 0.037 vs. 2.13 ± 0.037) and TIMP‐1 (0.76 ± 0.093 vs. 1.99 ± 0.12) protein levels. Furthermore, overexpression of prolyl‐hydroxylase 2 (PHD2) transgene, an enzyme promoting the degradation of HIF‐1α, significantly attenuated albumin‐induced increases in collagen‐ I(0.53 ± 0.21 vs. 1.81 ± 0.30) and TIMP‐1 (0.59 ± 0.19 vs. 1.23 ± 0.16) levels, whereas silencing of PHD2 gene remarkably enhanced albumin‐induced increase in collagen‐I level (2.48 ± 0.77 vs. 1.81 ± 0.30). It is suggested that HIF‐1α mediates albumin‐induced profibrotic effects in renal tubular cells and that manipulating PHD2/HIF‐1α pathway may be used as a therapeutic strategy in chronic kidney diseases.Grant Funding Source: support by NIH grant HL089563 and HL106042