SIRT1 attenuates renal fibrosis by repressing HIF-2α

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase belonging to class III histone deacetylases. Previous studies have shown that SIRT1 is involved in kidney physiology regulation and protects the kidney from various pathological factors. However, the underlying mechanisms behind its function have yet to be fully elucidated. In our study, we found that ablation of Sirt1 in renal interstitial cells resulted in more severe renal damage and fibrosis in unilateral ureteral obstruction (UUO) model mice. We also observed that hypoxia-inducible factor (HIF)-2 alpha expression was increased in Sirt1 conditional knockout mice, suggesting that HIF-2 alpha might be a substrate of SIRT1, mediating its renoprotective roles. Therefore, we bred Hif2a deficient mice and subjected them to renal trauma through UUO surgery, ultimately finding that Hif2a ablation attenuated renal fibrogenesis induced by UUO injury. Moreover, in cultured NRK-49F cells, activation of SIRT1 decreased HIF-2 alpha and fibrotic gene expressions, and inhibition of SIRT1 stimulated HIF-2 alpha and fibrotic gene expressions. Co-immunoprecipitation analysis revealed that SIRT1 directly interacted with and deacetylated HIF-2 alpha. Together, our data indicate that SIRT1 plays a protective role in renal damage and fibrosis, which is likely due to inhibition of HIF-2 alpha.

Automated summary

SIRT1 functions as a protective factor in renal damage and fibrosis by inhibiting the expression of HIF-2 alpha. Loss of SIRT1 leads to exacerbated kidney injury and fibrosis, while the substrate relationship between HIF-2 alpha and SIRT1 has been suggested in the study.