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BACKGROUND: 13% of African Americans have a high risk APOL1 genotype, carrying two risk alleles (G1/G1, G1/G2 or G2/G2). The mechanisms underlying nephropathy caused by these APOL1 risk variant genotypes are not fully understood. Downstream of gene function, homeostatic maintenance of a complex and interconnected network of metabolites is essential for normal kidney function. However, this metabolic network can be rerouted by genetic changes or environmental insults, both of which can contribute to development and/or progression of kidney diseases. APOL1 nephropathy exhibits both genetic and environmental triggers, but how APOL1 might alter metabolic homeostasis and how such changes may contribute to disease progression remains unclear.METHODS: APOL1 nephropathy was induced in human BAC transgenic APOL1 mice by IFN-γ adenovirus. Non-targeted metabolomics was performed on glomeruli from risk variant (G1/G1 and G2/G2) and non-risk variant (G0/G0) mice as well as on tetracycline-inducible cell lines expressing risk or non-risk variants. Metabolic signaling pathways in risk or non-risk groups were compared and transcriptional changes driving these metabolic differences were identified. Metabolic interventions were performed in both APOL1 risk and non-risk variant-expressing cells and in mice. The effect of metabolic intervention was evaluated by cytotoxicity assays and urine albumin-to-creatinine ratios for cellular and in vivo responses, respectively.RESULTS: Perturbed purine metabolism was the strongest metabolite differentiator between high- and low-risk APOL1 genotypes in cultured cells and in whole glomeruli. Expression of APOL1 G2/G2 downregulated the rate-limiting enzymes of purine biosynthesis and induced ATP depletion. In APOL1 G2/G2-expressing cells, supplementation with the purine biosynthesis precursor AICAr rescued purine biosynthesis, reduced cytotoxicity and boosted ATP. In interferon-γ treated APOL1 G2/G2 transgenic mice, AICAr administration boosted purine biosynthesis, decreased kidney pAMPK, and reduced albuminuria levels. AICAr treatment rescued G2 mouse podocyte death induced by the inflammatory stimuli of combined interferon-γ and Toll-like receptor 1/2 agonist.CONCLUSIONS: Increasing purine biosynthesis mitigated APOL1 risk-variant induced injury in cell and transgenic mouse models of APOL1 kidney disease.