Acute kidney injury (AKI) affects millions of patients worldwide, with a mortality rate exceeding 50%. While it is known that mitochondrial dysfunction contributes to tubular injury, treatments to hasten renal repair have been hindered by the lack of plausible pharmacologic targets. Marina Morigi and colleagues at the Mario Negri Institute for Pharmacological Research have uncovered a renoprotective role for the NAD-dependent deacetylase sirtuin 3 (SIRT3) and shown that pharmacologic activation of SIRT3 counteracts cisplatin-induced renal failure. In a cisplatin-induced murine model of AKI, treatment of WT mice with SIRT3-boosting drugs, including the AMPK agonist AICAR and the antioxidant acetyl-L-carnitine (ALCAR), decreased tubular injury and improved renal function. In contrast, administration of AICAR and ALCAR to SIRT3-null mice following cisplatin-induced injury did not improve survival. The authors determined that in addition to restoring SIRT3 activity, AICAR and ALCAR treatment decreased cisplatin-induced mitochondrial fragmentation. In vitro, SIRT3 preserved mitochondrial membrane integrity in cisplatin-treated human tubular cells by preventing aberrant membrane depolarization and mitophagy. Together, the results of this study provide insight into the role of SIRT3 in protection against AKI and suggest AICAR and ALCAR as potential therapeutic agents for limiting AKI-associated damage. The accompanying image shows representative transmission electron micrographs of the proximal renal tubules of WT (left) and cisplatin-treated mice (right), illustrating the decreased mitochondrial density and fragmentation in response to kidney injury.
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-
Marina Morigi, Luca Perico, Cinzia Rota, Lorena Longaretti, Sara Conti, Daniela Rottoli, Rubina Novelli, Giuseppe Remuzzi, Ariela Benigni