| First Author | Ryu DR | Year | 2019 |
| Journal | Aging Cell | Volume | 18 |
| Issue | 2 | Pages | e12904 |
| PubMed ID | 30614190 | Mgi Jnum | J:274020 |
| Mgi Id | MGI:6283210 | Doi | 10.1111/acel.12904 |
| Citation | Ryu DR, et al. (2019) Sirt1-hypoxia-inducible factor-1alpha interaction is a key mediator of tubulointerstitial damage in the aged kidney. Aging Cell 18(2):e12904 |
| abstractText | 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)-1alpha is largely unknown. In this study, we investigated whether HIF-1alpha 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-1alpha. The level of Bcl-2/adenovirus E1B-interacting protein 3, carbonic anhydrase 9, Snail, and transforming growth factor-beta1, which are regulated by HIF-1alpha, was significantly higher in aged mice suggesting that HIF-1alpha 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-1alpha. Resveratrol, a Sirt1 activator, effectively prevented hypoxia-induced production of ECM proteins, mitochondrial damage, reactive oxygen species generation, and apoptosis. The inhibition of HIF-1alpha activity by Sirt1-induced deacetylation of HIF-1alpha was confirmed by Sirt1 overexpression under hypoxic conditions and by resveratrol treatment or Sirt1 overexpression in HIF-1alpha-transfected HK-2 cells. Finally, we confirmed that chronic activation of HIF-1alpha promoted apoptosis and fibrosis, using tubular cell-specific HIF-1alpha transgenic mice. Taken together, our data suggest that Sirt1-induced deacetylation of HIF-1alpha may have protective effects against tubulointerstitial damage in aged kidney. |
