View : 40 Download: 0

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

Title
Sirt1-hypoxia-inducible factor-1 alpha interaction is a key mediator of tubulointerstitial damage in the aged kidney
Authors
Ryu, Dong RyeolYu, Mi RaKong, Kyoung HyeKim, HyoungnaeKwon, Soon HyoJeon, Jin SeokHan, Dong CheolNoh, Hyunjin
Ewha Authors
류동열
SCOPUS Author ID
류동열scopus
Issue Date
2019
Journal Title
AGING CELL
ISSN
1474-9718JCR Link

1474-9726JCR Link
Citation
AGING CELL vol. 18, no. 2
Keywords
agedeacetylationHIF-1 alphaSirt1
Publisher
WILEY
Indexed
SCOPUS WOS scopus
Document Type
Article
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.
DOI
10.1111/acel.12904
Appears in Collections:
의과대학 > 의학과 > Journal papers
Files in This Item:
There are no files associated with this item.
Export
RIS (EndNote)
XLS (Excel)
XML


qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

BROWSE