SIRT1 activation by resveratrol ameliorates cisplatin-induced renal injury through deacetylation of p53

Abstract

Sung MJ, Kim W. SIRT1 activation by resveratrol ameliorates cisplatin-induced renal injury through deacetylation of p53. Am J Physiol Renal Physiol 301: F427-F435, 2011. First published May 18, 2011 doi:10.1152/ajprenal.00258.2010.-Nephrotoxicity is one of the important dose-limiting factors during cisplatin treatment. There is a growing body of evidence that activation of p53 has a critical role in cisplatin-induced renal apoptotic injury. The nicotinamide adenine dinucleotide-dependent protein deacetylase SIRT1 decreases apoptosis through deacetylating of p53, and resveratrol is known as an activator of SIRT1. To study the role of SIRT1 in cisplatin-induced renal injury through interaction with p53, mouse proximal tubular cells (MPT) were treated with cisplatin and examined the expression level of SIRT1, acetylation of p53, PUMA-␣, Bax, the cytosolic/ mitochondrial cytochrome c ratio, and active caspase-3. The expression of SIRT1 was decreased by cisplatin. Resveratrol, a SIRT1 activator, ameliorated cisplatin-induced acetylation of p53, apoptosis, and cytotoxicity in MPT cells. In addition, resveratrol remarkably blocked cisplatin-induced decrease of Bcl-xL in MPT cells. Further specific SIRT1 inhibition with EX 527 or small interference RNA specific to SIRT1 reversed the effect of resveratrol on cisplatininduced toxicity. Inhibition of p53 by pifithrin-␣ reversed the effect of EX527 in protein expression of PUMA-␣, Bcl-xL, and caspase-3 and cytotoxicity in MPT cells. SIRT1 protein expression after cisplatin treatment was significantly decreased in the kidney. SIRT1 activation by resveratrol decreased cisplatin-induced apoptosis while improving the glomerular filtration rate. Taken together, our findings suggest that the modulation of p53 by SIRT1 could be a possible target to attenuate cisplatin-induced kidney injury. apoptosis; cisplatin nephrotoxicity CISPLATIN IS A CHEMOTHERAPEUTIC agent widely used for the treatment of malignant tumors in solid organs. One of the important dose-limiting factors of cisplatin treatment is nephrotoxicity. Direct DNA damage, inflammatory injury, and oxidative stress have been recognized as the mechanism of cisplatin-induced renal injury. Especially, cisplatin-induced apoptotic cell death after DNA damage is the major mechanism in cytotoxicity in renal tubule cells.In response to DNA damage, p53 can induce cell cycle arrest and apoptosis. p53-induced apoptosis affects its transcriptional activity and Bcl2 family members in mitochondria (24). In kidney disease, p53 is involved in the apoptotic injury in ischemic injury and aristolochic acid-induced nephrotoxicity (11,30,33). There is also a growing body of evidence that p53 plays a critical role in cisplatin-induced renal injury (2, 9, 30). Furthermore, it has been demonstrated that downregulation of p53 by small interference (si) RNA is an effective way of preventing or treating cisplatin-induced nephrotoxicity (25). Activation of p53 is regulated by posttranslational modification of p53 such as ubiquitination, phosphorylati...

Sirtuin 1: A Target for Kidney Diseases

“…SIRT1 bound and deacetylated the C-terminal Lys382 of p53, which destabilized the p53 protein and reduced its transcriptional activity, resulting in the decrease of apoptosis (15,56,57). Resveratrol, a SIRT1 activator, was reported to ameliorate the acetylation of p53 and renal damage induced by diabetes and cisplatin (47,48). These findings suggest that the downregulation of p53 function by SIRT1 could be a possible strategy to attenuate oxidative stress-induced apoptosis of glomerular mesangial cells, podocytes and renal tubular cells.…”

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

“…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). Thus, it appears that SIRTs play a role in both renal protection and fibrogenesis.…”

Inhibition of STAT3 acetylation is associated with attenuated renal fibrosis in the obstructed kidney

“…One of the best characterized deacetylases is sirtuin 1 (SIRT1), a member of nicotinamide adenine dinucleotide (NAD + )-dependent class III protein deacetylases, which can be inhibited by nicotinamide [35,36] . SIRT1, which mediates the deacetylation of STAT3 Lys685 site [37][38][39][40][41] , can be activated by resveratrol (trans-3,4',5-trihydroxystilbene) [42,43] , a natural polyphenol with renal protective effects that depend on deacetylation of Smad3 [44] , p53 [45] , and NF-κB p65 [46] . However, the role of STAT3 acetylation in the antifibrotic activity of resveratrol has yet to be clarified.…”