Hypoxia inducible factor-1α mediates the profibrotic effect of albumin in renal tubular cells

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 been implicated in the progression of CKD. The present study tested the hypothesis that HIF-1α mediates albumin-induced profibrotic effect in cultured renal proximal tubular cells. Incubation of the cells with albumin (40 μg/ml) for 72 hrs significantly increased the protein levels of HIF-1α, tissue inhibitor of metalloproteinase (TIMP)-1 and collagen-I, which were blocked by HIF-1α shRNA. Albumin also stimulated an epithelial-mesenchymal transition (EMT) as indicated by the decrease in epithelial marker E-cadherin, and the increase in mesenchymal markers α-smooth muscle actin and fibroblast-specific protein 1. HIF-1α shRNA blocked albumin-induced changes in these EMT markers as well. Furthermore, albumin reduced the level of hydroxylated HIF-1α, indicating an inhibition of the activity of prolyl-hydroxylases, enzymes promoting the degradation of HIF-1α. An anti-oxidant ascorbate reversed albumin-induced inhibition of prolyl-hydroxylase activity. Overexpression of prolyl-hydroxylase 2 (PHD2) transgene, a predominant isoform of PHDs in renal tubules, to reduce HIF-1α level significantly attenuated albumin-induced increases in TIMP-1 and collagen-I levels. These results suggest that albumin-induced oxidative stress inhibits PHD activity to accumulate HIF-1α, which mediates albumin-induced profibrotic effects in renal tubular cells.

Deciphering the Pharmacological Mechanisms of Taohe-Chengqi Decoction Extract Against Renal Fibrosis Through Integrating Network Pharmacology and Experimental Validation In Vitro and In Vivo

“…Fibrosis causes microvasculature injury and inflammatory stimulation decreases oxygen permeation and increases renal tubular epithelial cells metabolism, which can lead to the persistent hypoxic condition of renal tissue. Conversely, hypoxia can trigger the apoptosis of renal tubular epithelial cells and stimulate the phenotype transformation from renal tubular cells to myofibroblasts (Hu et al, 2017;Liu et al, 2018;Shu et al, 2019). Hypoxia could also promote the expression of tissue inhibitors of metalloproteinases (TIMPS), which would inhibit the degradation of ECM, reduce the blood flow of capillaries around renal tubules and damage the diffusion of oxygen, thus aggravating the local hypoxia (Volker, 2009).…”

Long noncoding RNA NEAT1 is involved in the protective effect of Klotho on renal tubular epithelial cells in diabetic kidney disease through the ERK1/2 signaling pathway

“…In this study, we found that the expression of NEAT1 was significantly increased in both HFD-and STZ-induced DM mice and a BSA-induced fibrosis and EMT model in HK-2 cells. It has been reported that proteinuria can promote the progression of renal tubulointerstitial fibrosis and DKD 30,31 . BSA has been reported to induce renal proximal tubular cells to mimic tubulointerstitial fibrosis in vitro 32 .…”

MiR‐4756 promotes albumin‐induced renal tubular epithelial cell epithelial‐to‐mesenchymal transition and endoplasmic reticulum stress via targeting Sestrin2

“…Proteinuria is the primary feature of DKD and is positively correlated with the progression to end‐stage renal disease (Gross et al, ). It has been reported that the exposure of proximal tubular epithelial cells to excess proteins causes tubulointerstitial fibrosis and the progression of DKD (Allouch & Munusamy, ; Hu et al, ; Jheng et al, ; Nishi et al, ; Wu, He, Jing, Li, & Zhang, ). Furthermore, in the early stage of DKD, the onset of proteinuria causes tubular function and morphological injury (Thomas, Burns, & Cooper, ).…”