Abstract: FR-PO0191
MARY1 Restores Kidney Function, Attenuates Kidney Fibrosis, and Reduces Epithelial-Mesenchymal Transition Following AKI
Session Information
- AKI: Mechanisms - 2
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Victor Santiago Raj, Paul, R Ken Coit College of Pharmacy, University of Arizona, Tucson, Arizona, United States
- Janda, Jaroslav, R Ken Coit College of Pharmacy, University of Arizona, Tucson, Arizona, United States
- Girdhar, Ishika, R Ken Coit College of Pharmacy, University of Arizona, Tucson, Arizona, United States
- Schnellmann, Rick G., R Ken Coit College of Pharmacy, University of Arizona, Tucson, Arizona, United States
Background
Acute kidney injury (AKI) is a severe condition characterized by a sudden decline in renal function, leading to metabolic dysfunction, electrolyte imbalances, and systemic complications. Ischemia reperfusion (I/R) injury, hypovolemia, sepsis, and drug induced nephrotoxicity are common initiators of AKI. Recently, we reported a novel, potent and subtype-selective 5-HT2BR antagonist, MARY1, that induces MB in the kidney in vivo. In this study, the therapeutic potential of MARY1 in restoring renal function, attenuating renal fibrosis, and reducing epithelial-mesenchymal transition (EMT) in a mouse model of bilateral I/R-induced AKI was examined.
Methods
Male 8-10-weeks old, weighs 20-30 grams of C57B/6NCrl mice were administered either MARY1 (0.3mg/kg) or vehicle daily, beginning 24h after I/R-induced AKI and continuing for 6,12 and 30 days (n=6-8/group). Kidneys were harvested and cortical proteins were analyzed using 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
Following bilateral I/R induced AKI, serum creatinine, blood urea nitrogen, kidney injury molecule 1 (KIM1) and Lipocalin 2 (LCN2) were maximally elevated at 24 hours. Daily administration of MARY1 for 6 days post AKI decreased serum creatinine, blood urea nitrogen, KIM1, LCN2, and restored mitochondrial homeostasis compared to vehicle group. Immunoblot analysis revealed restoration of mitochondrial biogenic marker (PGC1α), mitochondrial dynamics proteins (MFN1, MFF, OPA1), and beta-oxidation proteins (ACADM, ACSM2A) in the kidney cortex. In addition, treatment with MARY1 for 12 and 30 days reduced markers of pro-inflammatory (NF-κB p65, Iκκ α+β), cell senescence (p53, p21) pro-fibrotic (COL1A1, COL3A1, TGFβ, αSMA), and markers of EMT transition (Vimentin, FSP1, MMP9) in the kidney cortex.
Conclusion
MARY1 restored mitochondrial homeostasis, beta oxidation proteins, renal function and recovery following AKI. MARY1 attenuates renal fibrosis, inflammation, senescence and EMT onset of acute kidney disease. Future experiments will determine the mechanism of action of MARY1 and efficacy in other kidney diseases (CKD, DN).
Funding
- Veterans Affairs Support