Sirt1 activation protects the mouse renal medulla from oxidative injury
Wenjuan He, … , Matthew D. Breyer, Chuan-Ming Hao
Wenjuan He, … , Matthew D. Breyer, Chuan-Ming Hao
Published March 24, 2010
Citation Information: J Clin Invest. 2010;120(4):1056-1068. https://doi.org/10.1172/JCI41563.
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Research Article

Sirt1 activation protects the mouse renal medulla from oxidative injury

Abstract

Sirtuin 1 (Sirt1) is a NAD+-dependent deacetylase that exerts many of the pleiotropic effects of oxidative metabolism. Due to local hypoxia and hypertonicity, the renal medulla is subject to extreme oxidative stress. Here, we set out to investigate the role of Sirt1 in the kidney. Our initial analysis indicated that it was abundantly expressed in mouse renal medullary interstitial cells in vivo. Knocking down Sirt1 expression in primary mouse renal medullary interstitial cells substantially reduced cellular resistance to oxidative stress, while pharmacologic Sirt1 activation using either resveratrol or SRT2183 improved cell survival in response to oxidative stress. The unilateral ureteral obstruction (UUO) model of kidney injury induced markedly more renal apoptosis and fibrosis in Sirt1+/– mice than in wild-type controls, while pharmacologic Sirt1 activation substantially attenuated apoptosis and fibrosis in wild-type mice. Moreover, Sirt1 deficiency attenuated oxidative stress–induced COX2 expression in cultured mouse renal medullary interstitial cells, and Sirt1+/– mice displayed reduced UUO-induced COX2 expression in vivo. Conversely, Sirt1 activation increased renal medullary interstitial cell COX2 expression both in vitro and in vivo. Furthermore, exogenous PGE2 markedly reduced apoptosis in Sirt1-deficient renal medullary interstitial cells following oxidative stress. Taken together, these results identify Sirt1 as an important protective factor for mouse renal medullary interstitial cells following oxidative stress and suggest that the protective function of Sirt1 is partly attributable to its regulation of COX2 induction. We therefore suggest that Sirt1 provides a potential therapeutic target to minimize renal medullary cell damage following oxidative stress.

Authors

Wenjuan He, Yingying Wang, Ming-Zhi Zhang, Li You, Linda S. Davis, Hong Fan, Hai-Chun Yang, Agnes B. Fogo, Roy Zent, Raymond C. Harris, Matthew D. Breyer, Chuan-Ming Hao

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Figure 6

Sirt1 activation is associated with reduced apoptosis and fibrosis in kidney subjected to ureteral obstruction.

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Sirt1 activation is associated with reduced apoptosis and fibrosis in ki...
(A) Representative images (original magnification, ×200) and quantification of TUNEL-positive apoptosis in the renal medulla of vehicle-treated or Sirt1 activator SRT1720–treated (100 mg/kg/d) wild-type mice 3 days after UUO (*P < 0.05). (B) Immunoblot for cleaved caspase-3 expression in the entire kidney of vehicle-treated or SRT1720-treated wild-type mice 3 days after UUO (n = 4, densitometry, *P < 0.0001 versus obstructed kidney of vehicle-treated mice). (C) Representative images (original magnification, ×200) and quantification of Sirius red staining on kidney sections of vehicle-treated or SRT1720-treated mice 7 days after UUO (*P < 0.05 versus obstructed kidney of vehicle-treated mice). (D) Levels of Col1 protein expression in the entire kidney of vehicle-treated or SRT1720-treated wild-type mice 7 days after UUO were assessed by immunoblot (n = 5, densitometry, *P < 0.05 versus obstructed kidney of vehicle-treated mice). V, vehicle; SRT, SRT1720.