Hypoxia-inducible factor-1α promotes glomerulosclerosis and regulates COL1A2 expression through interactions with Smad3

Abstract

The function of hypoxia-inducible factor-1α (HIF-1α) in chronic kidney disease is disputed. Here we report that interactions of HIF-1α with transforming growth factor beta (TGF-β) signaling may promote its fibrotic effects. Knockout of HIF-1α is protective against glomerulosclerosis and glomerular type-I collagen accumulation in a mouse podocyte ablation model. Transcriptional analysis of cultured renal cells showed that α2(I) collagen expression is directly regulated by HIF-1α binding to a functional hypoxia-responsive element in its promoter at −335 relative to the transcription start site. Activation of COL1A2 transcription by HIF-1α occurred in the absence of hypoxia, and is strongly enhanced by TGF-β signaling. TGF-β, in addition to increasing HIF-1α levels increased both HIF-1α binding to the COL1A2 promoter and HIF-1α N-terminal transactivation domain activity. These effects of TGF-β on HIF-1α were inhibited in Smad3-null mouse embryonic fibroblasts, suggesting a requirement for Smad3. Phosphorylated Smad3 also associated with the −335 hypoxia-responsive element of the COL1A2 promoter independent of a Smad DNA binding sequence. Smad3 binding to the −335 hypoxia-responsive element required HIF-1α both in vitro and in kidney lysate from the disease model suggesting formation of a HIF-1α-Smad3 transcriptional complex. Thus, HIF-1α-Smad3 have a novel interaction in glomerulosclerosis.

Hypoxia‐inducible factor 1‐alpha (HIF‐1α) as a factor mediating the relationship between obesity and heart failure with preserved ejection fraction

“…TSP‐1 is associated with cardiac fibrosis in ischaemia and is a potent activator of TGF‐β1 . COLIA2 is a subunit of collagen that undergoes extracellular processing to become ECM and thus, contributes to fibrosis . HIF‐1α stimulates a COLIA2 promoter leading to increased accumulation of collagen subunits in human tubular epithelial cells contributing to glomerular sclerosis .…”

The Tubulointerstitial Pathophysiology of Progressive Kidney Disease

“…Genetic manipulation of HIF-1α expression in mice has demonstrated that HIF is profibrotic in several mouse models of progressive CKD. 43,50,51 However, inhibition of HIF exacerbates injury in several other models. 52–55 While it is possible that these results are model dependent, the general trend suggests that HIFs play a role in protecting the kidney against acute hypoxic injury, whereas they may play a deleterious role in more chronic, fibrotic injury.…”

“…92 The decrease in mitochondria further decreases ATP generation. While the source of intracellular ROS remains somewhat controversial, 101–103 one downstream mediator of ROS actions is the stabilization and generation of HIF , which promotes extracellular matrix expression 50 and decreases cell metabolic rates further. With decreased tubular function, less local generation of pro-angiogenic factors such as VEGF leads to decreased health of the peritubular vasculature, 104 further promoting hypoxia and HIF expression.…”

Role of hypoxia‐inducible factor 1α as a potential biomarker for renal diseases—A systematic review

“…Baumann et al reported, in an animal experiment, that increased HIF‐1α expression potentiates the damage caused by specific TGF‐β‐mediated kidney diseases and found a strong correlation between the COL1A2 gene‐regulating HIF‐1α in response to TGF‐β.…”

“…Therefore, HIF-1α regulates the activity of AMPK and contributes to the improvement of kidney function, which corroborates the study of Chen et al 68 Using the small interference RNA technique (SiRNA) for the HIF-1α gene, Chen et al 68 studies, these markers may interact directly with the expression of HIF. 52,68,69,74,76 Baumann et al 77 reported, in an animal experiment, that increased HIF-1α expression potentiates the damage caused by specific TGF-βmediated kidney diseases and found a strong correlation between the COL1A2 gene-regulating HIF-1α in response to TGF-β.…”