%0 Journal Article
%T Sirt1¨Chypoxia©\inducible factor©\1¦Á interaction is a key mediator of tubulointerstitial damage in the aged kidney
%A Dong Ryeol Ryu
%A Hyoungnae Kim
%A Hyunjin Noh
%A Jin Seok Jeon
%A Kyoung Hye Kong
%A Mi Ra Yu
%A Soon Hyo Kwon
%J Archive of "Aging Cell".
%D 2019
%R 10.1111/acel.12904
%X 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¦Á is largely unknown. In this study, we investigated whether HIF©\1¦Á 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¦Á. The level of Bcl©\2/adenovirus E1B©\interacting protein 3, carbonic anhydrase 9, Snail, and transforming growth factor©\¦Â1, which are regulated by HIF©\1¦Á, was significantly higher in aged mice suggesting that HIF©\1¦Á 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¦Á. 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¦Á activity by Sirt1©\induced deacetylation of HIF©\1¦Á was confirmed by Sirt1 overexpression under hypoxic conditions and by resveratrol treatment or Sirt1 overexpression in HIF©\1¦Á©\transfected HK©\2 cells. Finally, we confirmed that chronic activation of HIF©\1¦Á promoted apoptosis and fibrosis, using tubular cell©\specific HIF©\1¦Á transgenic mice. Taken together, our data suggest that Sirt1©\induced deacetylation of HIF©\1¦Á may have protective effects against tubulointerstitial damage in aged kidney
%K age
%K deacetylation
%K HIF©\1¦Á
%K Sirt1
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413666/