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.
Sirtuin 3-dependent mitochondrial dynamic improvements protect against acute kidney injury / M. Morigi, L. Perico, C. Rota, L. Longaretti, S. Conti, D. Rottoli, R. Novelli, G. Remuzzi, A. Benigni. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 0021-9738. - 125:2(2015 Feb), pp. 715-726.
|Titolo:||Sirtuin 3-dependent mitochondrial dynamic improvements protect against acute kidney injury|
REMUZZI, GIUSEPPE (Penultimo)
|Parole Chiave:||Acetylcarnitine; Acute Kidney Injury; Animals; Antineoplastic Agents; Antioxidants; Cell Line; Cisplatin; Humans; Kidney Tubules, Proximal; Mice; Mice, Knockout; Mitochondria; Oxidative Stress; Sirtuin 3; Vitamin B Complex; Mitochondrial Dynamics|
|Settore Scientifico Disciplinare:||Settore MED/14 - Nefrologia|
|Data di pubblicazione:||feb-2015|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1172/JCI77632|
|Appare nelle tipologie:||01 - Articolo su periodico|