Sirt1-hypoxia-inducible factor-1 alpha interaction is a key mediator of tubulointerstitial damage in the aged kidney

Abstract

Although it is known that the expression and activity of sirtuin 1 (Sirt1) decrease in the aged kidney, the role of interaction between Sirt1 and hypoxia-inducible factor (HIF)-1 alpha is largely unknown. In this study, we investigated whether HIF-1 alpha could be a deacetylation target of Sirt1 and the effect of their interaction on age-associated renal injury. Five-week-old (young) and 24-month-old (old) C57Bl/6J mice were assessed for their age-associated changes. Kidneys from aged mice showed increased infiltration of CD68-positive macrophages, higher expression of extracellular matrix (ECM) proteins, and more apoptosis than young controls. They also showed decreased Sirt1 expression along with increased acetylated HIF-1 alpha. The level of Bcl-2/adenovirus E1B-interacting protein 3, carbonic anhydrase 9, Snail, and transforming growth factor-beta 1, which are regulated by HIF-1 alpha, was significantly higher in aged mice suggesting that HIF-1 alpha activity was increased. In HK-2 cells, Sirt1 inhibitor sirtinol and siRNA-mediated knockdown of Sirt1 enhanced apoptosis and ECM accumulation. During hypoxia, Sirt1 was down-regulated, which allowed the acetylation and activation of HIF-1 alpha. Resveratrol, a Sirt1 activator, effectively prevented hypoxia-induced production of ECM proteins, mitochondrial damage, reactive oxygen species generation, and apoptosis. The inhibition of HIF-1 alpha activity by Sirt1-induced deacetylation of HIF-1 alpha was confirmed by Sirt1 overexpression under hypoxic conditions and by resveratrol treatment or Sirt1 overexpression in HIF-1 alpha-transfected HK-2 cells. Finally, we confirmed that chronic activation of HIF-1 alpha promoted apoptosis and fibrosis, using tubular cell-specific HIF-1 alpha transgenic mice. Taken together, our data suggest that Sirt1-induced deacetylation of HIF-1 alpha may have protective effects against tubulointerstitial damage in aged kidney.