The histone deacetylase, SIRT1, contributes to the resistance of young mice to ischemia/reperfusion-induced acute kidney injury

Abstract

Acute kidney injury (AKI) is a critical condition with a mortality rate as high as 50% and significantly contributes to the burden of end-stage renal disease (ESRD) requiring renal replacement therapy. The incidence and prognosis of AKI have been shown to vary with patient age, with younger individuals being more resistant to AKI. In mice, clamping the renal artery for 45 min causes substantial kidney damage in 4-month-old animals but only mild renal injury in 2-month-old animals. Here, younger mice were found to express higher levels of the NAD(+)-dependent histone deacetylase SIRT1 in the kidney. A small molecule SIRT1 activator, SRT-1720, markedly improved renal tubular pathology and overall renal function in adult mice following ischemia/reperfusion. Genetic ablation of one allele (SIRT1(+/-)) significantly enhanced the level of kidney damage relative to that in wild-type (SIRT1(+/+)) mice. The mechanisms underlying the protective effect of SIRT1 included the suppression of cell apoptosis. Hence, our results suggest that SIRT1 might be a novel therapeutic target for ischemia/reperfusion-induced kidney damage.

Blocking Sirtuin 1 and 2 Inhibits Renal Interstitial Fibroblast Activation and Attenuates Renal Interstitial Fibrosis in Obstructive Nephropathy

“…SIRTs have been reported to be involved in renal protection, antiaging, and neuron survival (He et al, 2010;Villalba and Alcain, 2012;Fan et al, 2013). However, the role of SIRTs, particularly individual isoforms, in renal interstitial fibroblast activation and renal fibrosis development is not well defined.…”

“…In contrast to the role of SIRTs in mediating renal fibrogenesis, activation of SIRTs, in particular SIRT1, has been reported to protect against acute kidney injury induced by ischemia/reperfusion (Fan et al, 2013). The protective effect of SIRT1 is associated with maintaining peroxisome function, promoting mitochondrial biogenesis (Funk and Schnellmann, 2013) and deacetylation of p53 (Kim et al, 2011).…”

Calorie restriction and sirtuins revisited

“…In mice, SIRT1 genetic activation in transgenic mice or the application of STACs protects against various models of kidney injury (Funk et al 2010;Hasegawa et al 2010;He et al 2010;Fan et al 2013;Kim et al 2013). SIRT1 also mitigates fibrosis following acute kidney injury by deacetylating Smad 4 and suppressing TGF-b signaling ).…”

Follicle aging: a question of stress?

“…Seven members of the sirtuin family have been identified in mammals (SIRT1-7) [for an extensive review, see (17)]. Strong experimental evidence supports the notion that SIRT1 plays a crucial role in sensing and modulating the cellular redox status so providing protective effects in cells and tissues exposed to oxidative stressors in vitro and in vivo (18). SIRT1 is able to directly deacetylate key proteins involved in the cellular stress response, such as forkhead box O (FoxO) transcription factors.…”