Abstract
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)-2α expression was increased in Sirt1 conditional knockout mice, suggesting that HIF-2α 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-2α and fibrotic gene expressions, and inhibition of SIRT1 stimulated HIF-2α and fibrotic gene expressions. Co-immunoprecipitation analysis revealed that SIRT1 directly interacted with and deacetylated HIF-2α. Together, our data indicate that SIRT1 plays a protective role in renal damage and fibrosis, which is likely due to inhibition of HIF-2α.
Highlights
Chronic kidney disease (CKD) is a general term that encompasses multifarious disease pathways leading to irreversible changes in kidney function and structure over the course of months or years[1]
The results showed that hypoxia-inducible factor (HIF)-2α protein expression was increased in the kidneys of all mice subjected to ureteral obstruction (UUO) surgery, with a greater increase in Sirt[1] conditional knockout (CKO) mice (Fig. 4a, b)
Changes in Blood urea nitrogen (BUN) levels were consistent with the data of western blot and Masson’s trichrome staining (Fig. 6c). These results indicate that conditional knockout of Hif2a in interstitial cells ameliorates UUO-induced renal fibrosis and injury
Summary
Chronic kidney disease (CKD) is a general term that encompasses multifarious disease pathways leading to irreversible changes in kidney function and structure over the course of months or years[1]. Renal fibrosis is a chronic and progressive process that alters kidney function and structure, serving as the shared final pathway of most CKD conditions, irrespective of cause[4]. Previous studies have shown that SIRT1 is expressed in the kidney and plays beneficial roles in renal physiology and pathology[6,7,8,9]. SIRT1 has been shown to have antifibrotic functions in several animal models. He et al found that SIRT1 prevents kidney tissue from engaging in fibrogenesis by regulating oxidative stress-induced COX2 expression in UUO model mice[6]. Our previous results showed that, by inhibiting the transcriptional activity of Smad[3], SIRT1 plays a protective role against renal fibrosis in a CKD rodent model[10]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call