MARY1 Promotes Recovery from Acute Kidney Injury through Induction of Mitochondrial Biogenesis

Abstract ID 95561 Poster Board 067 Background: Acute kidney injury (AKI) is defined as a sudden and rapid loss of kidney function which is accompanied by elevated serum creatinine and mitochondrial dysfunction. Ischemia reperfusion (I/R) injury, sepsis, hypovolemia and drug induced nephrotoxicity are common initiators of AKI. AKI is an important public health concern with no FDA-approved treatments. We have shown that a number of pharmacological agents stimulate mitochondrial biogenesis (MB) and accelerate renal recovery in a mouse model of AKI. We have synthesized a new small molecule, MARY1, and examined MB and renal recovery of MARY1 following I/R induced AKI in mice. Methods: Male 8–10-week-old C57B/6NCrl mice were administered 0.3mg/kg of MARY1 or normal saline 24h following I/R and then every 24h over a 144h period (n = 6/group). Kidneys were harvested and snapped frozen in liquid nitrogen. Renal cortex samples were used to analyze gene expression (qRT-PCR) and protein expression (immunoblot) post AKI. One way ANOVA followed by TUKEY multiple comparison test was used to determine statistical significance between treatment groups. A p-value of p≤0.05 was used to identify statistical changes. Results: Serum creatinine and Kidney Injury Molecule-1 (KIM-1) was measured and found to be maximally increased at 24h post I/R. Over 144h, MARY1 treatment exhibited greater decrease in serum creatinine and KIM1 compared to vehicle control. MARY1 restored PGC1 α, master regulator of MB, mitochondrial dynamics proteins (MFN1, MFN2) mitochondrial copy number, mitochondrial complex proteins and total ATP at 144h. Transmission electron microscopy also revealed a decrease in the mitochondrial damage score following administration of MARY1 for 144h. Interestingly, administration of MARY1 also restored markers of key mitochondrial proteins involved in fatty acid oxidation. Conclusion: MARY1 restored mitochondrial homeostasis and accelerated renal recovery following I/R induced AKI in mice. Additional studies are needed to elucidate the cellular mechanism and the mechanism of renal recovery/function.