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Sirtuin 3–dependent mitochondrial dynamic improvements protect against acute kidney injury
Marina Morigi, … , Giuseppe Remuzzi, Ariela Benigni
Marina Morigi, … , Giuseppe Remuzzi, Ariela Benigni
Published January 20, 2015
Citation Information: J Clin Invest. 2015;125(2):715-726. https://doi.org/10.1172/JCI77632.
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Research Article Nephrology Article has an altmetric score of 5

Sirtuin 3–dependent mitochondrial dynamic improvements protect against acute kidney injury

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Abstract

Acute kidney injury (AKI) is a public health concern with an annual mortality rate that exceeds those of breast and prostate cancer, heart failure, and diabetes combined. Oxidative stress and mitochondrial damage are drivers of AKI-associated pathology; however, the pathways that mediate these events are poorly defined. Here, using a murine cisplatin-induced AKI model, we determined that both oxidative stress and mitochondrial damage are associated with reduced levels of renal sirtuin 3 (SIRT3). Treatment with the AMPK agonist AICAR or the antioxidant agent acetyl-l-carnitine (ALCAR) restored SIRT3 expression and activity, improved renal function, and decreased tubular injury in WT animals, but had no effect in Sirt3–/– mice. Moreover, Sirt3-deficient mice given cisplatin experienced more severe AKI than WT animals and died, and neither AICAR nor ALCAR treatment prevented death in Sirt3–/– AKI mice. In cultured human tubular cells, cisplatin reduced SIRT3, resulting in mitochondrial fragmentation, while restoration of SIRT3 with AICAR and ALCAR improved cisplatin-induced mitochondrial dysfunction. Together, our results indicate that SIRT3 is protective against AKI and suggest that enhancing SIRT3 to improve mitochondrial dynamics has potential as a strategy for improving outcomes of renal injury.

Authors

Marina Morigi, Luca Perico, Cinzia Rota, Lorena Longaretti, Sara Conti, Daniela Rottoli, Rubina Novelli, Giuseppe Remuzzi, Ariela Benigni

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Figure 2

AMPK agonist AICAR exerts renoprotection in mice with AKI by increasing SIRT3.

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AMPK agonist AICAR exerts renoprotection in mice with AKI by increasing ...
(A) Western blot and densitometric analysis of pAMPKα and total AMPKα in the renal tissue of control and cisplatin-treated mice given saline or AICAR at 4 days. *P < 0.05, ANOVA corrected with Bonferroni coefficient. n = 5 control mice; n = 7 cisplatin mice+saline; n = 6 cisplatin mice+AICAR. (B) Renal function in control mice and cisplatin-treated mice receiving saline or AICAR at 4 days. ***P < 0.001, ANOVA corrected with Bonferroni coefficient. n = 7 control mice; n = 8 cisplatin mice+saline; n = 8 cisplatin mice+AICAR. (C) Effect of AICAR treatment on renal histological changes at 4 days evaluated as number of cast and necrotic tubules per HPF. ***P < 0.001, ANOVA corrected with Bonferroni coefficient. n = 6 mice per group. (D) Renal expression of Nampt, Pgc1a, and Sirt3 transcripts studied by real-time PCR in control and cisplatin-treated mice given saline or AICAR at 4 days. *P < 0.05, **P < 0.01, and ***P < 0.001, ANOVA corrected with Bonferroni coefficient. n = 6 mice per group. (E) Representative images of SIRT3 protein staining (green) in proximal tubules of control and cisplatin-treated mice given saline or AICAR at 4 days. Scale bars: 10 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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