Hypoxia-inducible factor-1α regulates renal fibrosis in mice with chronic kidney disease by inducing miR-126/JAK2-STAT3 axis
Objective:To investigate the molecular mechanism of hypoxia-inducible factor-1α(HIF-1α)promoting renal fibrosis in mice with chronic kidney disease by inducing miR-126/JAK2-STAT3 axis.Methods:Male C57/BL6 mice at 8 weeks old were divided into sham operation,model,HIF-1α mimic,miR-126 mimic,HIF-1α+miR mimic,WP1066,and miR-126 mimic+WP1066 groups.Using a fully automated biochemical analyzer,24-hour urinary protein,blood urea nitrogen(BUN),and serum creatinine(SCr)levels were measured in the mouse kidneys.MiR-126 expression in kidney tissues was assessed via qRT-PCR,and HIF-α expression,along with renal fibrosis-related proteins(fibronectin,collagen-Ⅰ,α-SMA),and key proteins in the JAK2/STAT3 signaling pathway were detected through immunoblotting.Masson staining aided in the analysis of renal pathology and interstitial fibrosis in mice.Results:The expression of miR-126 was inhibited after UUO model was established,and the difference was statistically significant.Compared with the sham operation group,mice in the model group exhibited elevated levels of 24-hour urinary protein,BUN,and SCr.There was evident disruption in the structure of renal tubules and interstitium,accompanied by marked renal fibrosis.Expression levels of fibronectin,collagen-Ⅰ,α-SMA,p-JAK2,and p-STAT3 were up-regulated.Furthermore,overexpression of HIF-1α further elevated the expression of 24-hour urinary protein,BUN,SCr,fibronectin,collagen-Ⅰ,α-SMA,p-JAK2,and p-STAT3.Conversely,overexpression of miR-126 led to downregulation of these parameters.Additionally,overexpression of HIF-1α could reverse the inhibitory effect of miR-126 overexpression on renal fibrosis,with statistical significance.Compared with the model group,blockade of the JAK2/STAT3 signaling pathway resulted in significant downregulation of p-JAK2,p-STAT3,fibronectin,collagen-Ⅰ,and α-SMA expression.Conclusions:Mouse renal fibrosis promotes high expression of HIF-1α in renal tissue,and HIF-1α enhances the activity of JAK2-STAT3 signaling pathway by inhibiting miR-126,ultimately promoting the progression of renal fibrosis.
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