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 1

Mitochondrial dysregulation and SIRT3 expression in mice with cisplatin-induced AKI.

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Mitochondrial dysregulation and SIRT3 expression in mice with cisplatin-...
(A) Representative transmission electron micrographs of the ultrastructure of mouse proximal tubular cells obtained from resin-embedded kidney sections of control and cisplatin-treated (Cispl) mice at 4 days. Scale bars: 2 μm. (B and C) Quantification of mitochondria per volume (n/μm3) and mean mitochondrial volume (μm3) by morphometric analysis in proximal tubular cells of control and cisplatin-treated mice. **P < 0.01, unpaired Student’s t test. n = 6 mice per group. (D) Staining score of nitrotyrosine, a marker of peroxynitrite, assessed in kidney cortex of control and cisplatin-treated mice. ***P < 0.001, unpaired Student’s t test. n = 5 mice per group. (E) Whole kidney expression of Sirt3 mRNA analyzed by real-time PCR in control and cisplatin-treated mice. ***P < 0.001, unpaired Student’s t test. n = 6 mice per group.