A Novel Pharmacological Agent, MARY1, Induces Mitochondrial Biogenesis and Restores Kidney Recovery in a Mouse Model of AKI

Background: Acute kidney injury (AKI) is a rapid decline in renal function that can increase mortality and morbidity. Ischemia reperfusion (I/R) injury, hypovolemia and drug induced nephrotoxicity are common initiators of AKI. As there is no FDA-approved drug for the treatment of AKI, we have studied chemicals that induce mitochondrial biogenesis (MB), generation of new functional mitochondria, and restore renal function and recovery following AKI. A novel small molecule, MARY1, was tested in vitro and in vivo for MB, and restoration of vascular integrity and renal function following I/R induced AKI in mice. Methods: Male ~7-8-week-old C57B/6NCrl mice were administered either MARY1 (0.3mg/kg) or vehicle daily, beginning 24h after I/R-induced AKI and continuing for 6 days (n=4-6/group). Kidneys were harvested, and gene and protein expression were analyzed using q-RT-PCR and immunoblot analysis. 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 and correct for multiple comparisons. Results: MARY1 induced MB in primary cultured renal proximal tubule cells and in naive mice. Following bilateral I/R induced AKI, serum creatinine, kidney injury molecule 1 (KIM1) and Lipocalin 2 (LCN2) were maximally elevated at 24h. Daily administration of MARY1 for 6 days post AKI decreased serum creatinine, KIM1, LCN2, microvascular leakage and mitochondrial damage score compared to vehicle group. qRT-PCR and immunoblot analysis revealed restoration of PGC1α, mitochondrial proteins (OXPHOS, NDUFB8, TFAM), mitochondrial copy number and total ATP in kidney cortex. In addition, treatment with MARY1 for 6 days restored beta oxidation proteins (AMPKα, ACSM2A, ACADM), tight junction proteins (CLDN1, CLDN2, CD9) and cell senescence (p21) in kidney cortex in mice. Interestingly, administration of MARY1 for 6 days post I/R injury had no effect on inflammation markers such as NF-κB and its downstream pro-inflammatory cytokines and eNOS in kidney cortex in mice. Conclusion: MARY1 restored mitochondrial, vascular, renal function and recovery through the induction of MB. However, MARY1 had no effect on inflammation. Future experiments will determine the efficacy of MARY1 in other kidney diseases (CKD, DN). Funding: Veterans Affairs Support