233 Metformin Increases Mitochondrial Coupling and Enhances Antioxidant Activity in the Kidneys of Aged Mice Following Thermal Trauma

Following thermal trauma, a systemic increase in pro-inflammatory mediators and hyperglycemia may culminate in multiple organ dysfunction, sepsis, and ultimately, death. This is particularly true in the elderly population, who are prone to organ failure and adverse outcomes following burn injury. We have recently demonstrated that in patients, metformin administration is equal to insulin in its ability to limit stress-induced hyperglycemia, yet the effects of this agent at the organ and cellular levels have not been thoroughly explored. As acute kidney injury (AKI) and kidney dysfunction are linked to high mortality after traumatic events, we investigated metformin’s benefits on these organs following burn injury in a murine model. Both 8 week (adult) and 50 week (aged) old C57BL/6 mice received a 30% total body surface area dorsal (98°C for 10 sec) and ventral (98°C for 2 sec) scald burn. Select mice received daily intraperitoneal injections post-burn of metformin (100 mg/kg) and kidneys were collected on day 7 post-trauma. Using a Seahorse XF96 extracellular flux analyzer and in-gel activity assays, metformin’s effects on kidney bioenergetics were probed. Changes in levels of oxidized proteins, lipids and nitrosylated proteins were monitored, as well as the activity of the antioxidant enzymes MnSOD, glutathione peroxidase and catalase. Serum creatinine levels were analyzed to assess kidney dysfunction. While kidney damage and dysfunction was not observed in the adult group, the aged cohort demonstrated increased oxidative damage and uncoupling following burn trauma. A 7 day regimen of metformin in these mice lowered oxidative damage and mitochondrial uncoupling while bolstering the activities of antioxidant enzymes. Given the prevalence of mitochondria in the kidneys and the need for aerobic ATP production in this organ, dysfunctional bioenergetics are likely a strong contributing factor to organ failure post-burn. Here, we show that metformin’s effects on mitochondria and antioxidative defense systems may reduce the incidence of kidney dysfunction in the elderly. The data herein demonstrate that metformin treatment in aged animals enhances mitochondrial function and lowers oxidative damage after burn trauma, thus supporting the continued use of this agent in elderly patients.