Mitochondria and metabolism in kidney disease

Ut Southwestern Medical Center, Dallas TX

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Abstract

PROJECT SUMMARY Background: The coenzyme and metabolic substrate nicotinamide adenine dinucleotide (NAD+) is involved in hundreds of cellular reactions. Work from many groups now link acquired deficiency in NAD+ biosynthesis to enhanced susceptibility to acute kidney injury (AKI). Whether the benefits of NAD+ augmentation extend to chronic kidney disease is contested in the literature. Others and we observe persistent suppression from onset of AKI through to late time points of a critical bottleneck enzyme in one of the NAD+ biosynthetic pathways, quinolinate phosphoribosyltransferase (QPRT). This enzyme participates in an eight-step conversion of dietary tryptophan to NAD+. Among major organs, significant flux through this pathway is restricted in mammals to the kidney and liver. QPRT is the body’s sole metabolizing enzyme for quinolinic acid (Quin). Concomitant with persistent suppression of QPRT, systemic and renal levels of Quin accumulate in AKI and CKD, reaching a remarkable twenty-fold elevation in human circulation as CKD transitions to end-stage disease. Little is known about the renal biology of Quin; however, our preliminary data show that excess Quin is alone nephrotoxic, that excess Quin exacerbates renal fibrosis, that NAD+ augmentation cannot rescue late outcomes of AKI—whereas Quin disposal via QPRT can—and that even low concentrations of Quin can promote potent deleterious effects on multiple renal cell types. Hypothesis: In this application, we will test the central hypothesis that persistent suppression of the Trp- dependent biosynthetic pathway after an AKI insult results in Quin buildup to promote adverse late outcomes. Aims: Three Aims are proposed: (1) to test intra- vs. extra-renal strategies to deplete Quin in AKI models to examine prevention of AKI; (2) to compare the benefits of distinct renal tubular NAD+ biosynthetic pathways in the prevention and treatment of AKI by implementing inducible, tissue-specific transgenic models; and (3) to elucidate mechanisms of Quin nephrotoxicity through a combination of candidate and systems based approaches. Outcomes: To support these parallel Aims, we are joined by established collaborators and experts in the domains of metabolic assays, mitochondrial assessments, and experimental liver biology. The experiments span cells and in vivo models to address innovative, fundamental scientific questions that hold translational significance. Successful execution of this project may catalyze new pharmacological and nutritional approaches to foster resilience to acute kidney stress.