Protective Effect of Methylthioadenosine Phosphorylase (MTAP) Inhibition in AKI

Background: Acute kidney injury (AKI) is sudden kidney failure, ranging from minor to severe, with multiple etiolgies. We identified adenine as a factor in diabetic kidney disease pathology, but its role in AKI is unknown. This study explores AKI metabolic mechanisms, focusing on adenine and the protective effects of inhibiting MTAP, the enzyme responsible for its production. Methods: Male mice with ischemia-reperfusion injury (IRI) were prophylactically treated with dapaglifozin (10mg/kg) or MT-DADMe-ImmA (MTDIA 20 mg/kg) or vehicles with sham-operated mice as controls. For cisplatin-induced AKI, mice received MTDIA or vehicle before cisplatin (20 mg/kg), with saline controls. Plasma and kidney metabolomics were performed using capillary electrophoresis and liquid chromatography-mass spectrometry. Results: Experimental IRI increased plasma metabolites, with adenine as the only nephrotoxic factor. Gene expression showed elevated inflammation and Mtap. Dapagliflozin modestly reduced kidney injury markers during ischemia, while MTAP inhibition significantly protected against AKI from IRI and cisplatin-induced models. MTAP inhibition normalized BUN, plasma creatinine levels and reduced kidney injury markers Kim-1 and Lcn2. PAS staining showed decreased necrotic tubules in MTDIA treated mice. MTAP inhibition reduced plasma LABA and pipecolate but not leucine and tyrosine. Kidney cortex adenine, pipecolate, GABA, and LABA were reduced, with increased MTA in MTDIA-treated mice. In cisplatin-induced AKI, MTDIA normalized BUN, Kim-1, and Lcn2 levels, and prevented tubular necrosis (Figure 1). Conclusion: This study highlights the metabolic changes from IRI and identifies MTAP inhibition as a protective strategy against AKI. MTAP inhibition mitigates metabolic changes and improves cellular stress responses, suggesting its potential as a therapeutic target. Funding: Other NIH Support - National Institutes of Health, National Center for Advancing Translational Sciences grant TL1 TR002647 (AS); National Institute of Diabetes and Digestive and Kidney Diseases UO1, 5U01DK114920-06 (KS), Veterans Affairs Support, Other U.S. Government SupportFigure 1. PAS staining of kidney FFPE sections (n=4/group) were evaluated blindly with quantification of necrotic tubules (average of 20 fields). IR30: 30 minutes bilateral ischemia. MTAPi: MTAP inhibitor (MTDIA).