ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: SA-PO732

Sirt1-Induced Hypoxia-Inducible Factor-1α Deacetylation Attenuates Tubulointerstitial Damage in Aged Kidney

Session Information

  • Geriatric Nephrology
    October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Geriatric Nephrology

  • 1100 Geriatric Nephrology

Authors

  • Noh, Hyunjin, Soon Chun Hyang Univ., Seoul, Korea (the Republic of)
  • Yu, Mi ra, Hyonam Kidney Laboratory, Seoul, Korea (the Republic of)
  • Ryu, Dong-Ryeol, Ewha Womans University, Seoul, Korea (the Republic of)
  • Kwon, Soon hyo, Soon Chun Hyang Univ., Seoul, Korea (the Republic of)
Background

Although it is well known that the expression and activity of Sirt-1 are decreased in the aged kidney, the role of interaction between Sirt-1 and hypoxia-inducible factor (HIF)-1 is largely unknown. Here, we investigated whether HIF-1α could be a deacetylation target of Sirt-1 and the effect of their interaction on age-associated renal injury.

Methods

Five-week-old (young) and 24-month-old (old) male C57Bl/6J mice were assessed for their age-associated changes. To clarify the underlying mechanisms, HK-2 cells were exposed to hypoxia. The effect of chronic activation of HIF-1α was investigated using tubular cell-specific HIF-1α transgenic mice.

Results

Kidneys from aged mice showed increased infiltration of CD68 positive macrophages, higher expression of extracellular matrix (ECM) proteins, and apoptosis than young controls. They also showed decreased expression of Sirt-1 along with increased acetylated HIF-1α. Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 level, which is regulated by HIF-1α, was significantly higher in aged mice suggesting that HIF-1α activity is increased. In HK-2 cells, Sirt-1 inhibitor sirtinol or siRNA-mediated knock-down of Sirt1 enhanced apoptosis and ECM accumulation whereas Sirt1 over-expression induced the opposite changes. During hypoxia, Sirt-1 was down-regulated, which allowed the acetylation and activation of HIF-1α. Resveratrol, a Sirt1 activator, effectively prevented hypoxia-induced production of ECM proteins, mitochondrial damage, reactive oxygen species generation, and apoptosis. The findings that Sirt1-induced deacetylation of HIF-1α inhibits HIF-1α activity were also confirmed by Sirt1 over-expression under hypoxic condition and by resveratrol treatment or Sirt1 over-expression in HIF-1α transfected HK-2 cells. Finally, we confirmed chronic activation of HIF-1α promoted apoptosis and fibrosis using tubular cell-specific HIF-1α transgenic mice.

Conclusion

Taken together, our data suggest that Sirt-1-induced deacetylation of HIF-1α may have protective effects against tubulointerstitial damage in aged kidney.

Funding

  • Government Support - Non-U.S.