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...

Oxidative stress and inflammation contribute to the pathogenesis of cisplatin-induced nephrotoxicity. We found that genistein, a tyrosine kinase inhibitor with broad specificities, and which also has estrogen-like activity, had protective effects on cisplatin-induced renal injury in mice. Genistein significantly decreased reactive oxygen species production, the expression of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 proteins, as well as the translocation of the p65 subunit of nuclear factor-kappaB into the nucleus and the infiltration of macrophages, all of which were increased in the kidney by cisplatin treatment. Genistein also decreased cisplatin-induced apoptosis by regulating p53 induction in kidney. Genistein significantly reduced reactive oxygen species production in cisplatin-treated normal human kidney HK-2 cells. These studies show that genistein or similar compounds might be useful in prevention of cisplatin-induced renal injury.

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These results indicate that cisplatin induces acute kidney injury by regulation of p53-dependent renal tubular apoptosis and that luteolin ameliorates the cisplatin-mediated nephrotoxicity through down-regulation of p53-dependent apoptotic pathway in the kidney.

Abstract-Fractalkine is a unique chemokine that functions as a chemoattractant as well as an adhesion molecule on endothelial cells activated by proinflammatory cytokines. Alpha-lipoic acid (LA), a naturally occurring dithiol compound, is an essential cofactor for mitochondrial bioenergetic enzymes. LA improves glycemic control, reduces diabetic polyneuropathies, and mitigates toxicity associated with heavy metal poisoning. The effects of LA on processes associated with sepsis, however, are unknown. We evaluated the antiinflammatory effect of LA on fractalkine expression in a lipopolysaccharide-induced endotoxemia model. Tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤) significantly induced fractalkine mRNA and protein expression in endothelial cells. LA strongly suppressed TNF-␣-or IL-1␤-induced fractalkine expression in endothelial cells by suppressing the activities of nuclear factor-B and specificity protein-1. LA also decreased TNF-␣-or IL-1␤-stimulated monocyte adhesion to human umbilical vein endothelial cells. As shown by immunohistochemistry, fractalkine protein expression was markedly increased by treatment with lipopolysaccharide in arterial endothelial cells, endocardium, and endothelium of intestinal villi. LA suppressed lipopolysaccharide-induced fractalkine protein expression and infiltration of endothelin 1-positive cells into the heart and intestine in vivo. LA protected against lipopolysaccharide-induced myocardial dysfunction and improved survival in lipopolysaccharide-induced endotoxemia. These results suggest that LA could be an effective agent to reduce fractalkine-mediated inflammatory processes in endotoxemia. Key Words: ␣-lipoic acid Ⅲ fractalkine Ⅲ endothelial cells Ⅲ inflammation S epsis is a clinical syndrome that represents the systemic response to an infection and is characterized by systemic inflammation and widespread tissue injury. At the site of injury, the endothelium expresses various adhesion molecules that attract leukocytes. 1 At the same time, inflammatory cells are activated and express a variety of adhesion molecules that cause the aggregation and margination of these cells to the vascular endothelium. 2 When the inflammatory response is initiated, a wide variety of chemical mediators are released into circulation. These chemical mediators, including tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤), are associated with the continuation of the inflammatory response. 3 Sepsis is caused mainly by an exaggerated systemic response to endotoxemia induced by gram-negative bacteria and their characteristic cell wall component, lipopolysaccharide (LPS). 4 In mice, challenge with high doses of LPS results in a syndrome resembling septic shock in humans. 5 Fractalkine (CX3CL1) is a structurally novel protein in which a soluble chemokine-like domain is fused to a mucin stalk that extends into the cytoplasm across the cell membrane. 6 Fractalkine is expressed in activated endothelial cells, and its expression is upregulated by TNF-␣, IL-1␤, and LPS. 7,8 As a full-...