Sirtuin 3–dependent mitochondrial dynamic improvements protect against acute kidney injury
Marina Morigi, Luca Perico, Cinzia Rota, Lorena Longaretti, Sara Conti, Daniela Rottoli, Rubina Novelli, Giuseppe Remuzzi, Ariela Benigni
Marina Morigi, Luca Perico, Cinzia Rota, Lorena Longaretti, Sara Conti, Daniela Rottoli, Rubina Novelli, Giuseppe Remuzzi, Ariela Benigni
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Research Article Nephrology

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

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 3

AICAR limits mitochondrial fragmentation and restores SIRT3 protein and activity.

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AICAR limits mitochondrial fragmentation and restores SIRT3 protein and ...
(A) Pattern of immunogold labeling for SIRT3 (arrows) in tubular cell mitochondria of control and cisplatin-treated mice given saline or AICAR at 4 days. Scale bars: 200 nm. (B) Representative transmission electron micrographs of the proximal tubular cell ultrastructure obtained from kidney sections of control and cisplatin-treated mice given saline or AICAR at 4 days. Scale bars: 5,000 nm. (C) Western blot and densitometric analysis of DRP1 protein expression in purified mitochondrial fraction isolated from renal tissue of control and cisplatin-treated mice given saline or AICAR at 4 days. VDAC protein expression was used as a sample loading control on the same membrane after stripping. **P < 0.01 and ***P < 0.001, ANOVA corrected with Bonferroni coefficient. Values are mean ± SEM (n = 3 mice per group). (D) Western blot (WB) and densitometric analysis of protein acetylation in mitochondria isolated from renal tissue of control and cisplatin-treated mice given saline or AICAR at 4 days. VDAC protein expression was used as a sample loading control on the same membrane after stripping. *P < 0.05 and **P < 0.01, ANOVA corrected with Bonferroni coefficient. Values are mean ± SEM (n = 3 mice per group). VDAC blots reported in C and D derived from the same gel.