title: 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.forename: Marina
authors.initials: M
authors.lastname: Morigi
authors.forename: Luca
authors.initials: L
authors.lastname: Perico
authors.forename: Cinzia
authors.initials: C
authors.lastname: Rota
authors.forename: Lorena
authors.initials: L
authors.lastname: Longaretti
authors.forename: Sara
authors.initials: S
authors.lastname: Conti
authors.forename: Daniela
authors.initials: D
authors.lastname: Rottoli
authors.forename: Rubina
authors.initials: R
authors.lastname: Novelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: Ariela
authors.initials: A
authors.lastname: Benigni
mesh_terms: D000108:Acetylcarnitine / Q000494:pharmacology; D058186:Acute Kidney Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D002945:Cisplatin / Q000493:pharmacokinetics; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D063154:Mitochondrial Dynamics; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D014803:Vitamin B Complex / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; C525046:Sirt3 protein, mouse; D014803:Vitamin B Complex; D000108:Acetylcarnitine; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D002945:Cisplatin