Exercise Training Has Striking Effects on the Kidney Proteome and Protects Kidney from Ischemic Injury: The MoTrPAC Study

Background: Chronic kidney disease (CKD) poses a significant global health threat due to increasing rates of CKD-related morbidity and mortality, emphasizing the need for interventions to mitigate its impact. While regular exercise training is broadly recognized to promote human metabolic health, the mechanisms by which exercise may provide protection from kidney disease are poorly understood. Methods: To elucidate the effects of exercise training on kidney, we first analyzed the data from MoTrPAC, the NIH-funded Molecular Transducers of Physical Activity Consortium, that investigates the multi-tissue molecular responses to exercise training in rats. Female rats underwent 4-8 weeks of treadmill exercise training, kidney collected and proteomics analysis performed. Next, we used a murine ischemic-reperfusion injury model (IRI) to determine the direct effects of exercise training on kidney. Female C57BL6J mice were housed in cages with or without running wheels for 11 days. Mice were then either sham or unilateral IRI-treated with no further access to running wheels. At 7 and 28 days post-IRI or sham, we conducted qPCR, western blotting, and kidney histological analysis. Results: Kidney proteomic analysis of MoTrPAC data showed that exercise training increased fatty acid β-oxidation (FAO) related proteins (e.g. Cpt1b, Acox1). Given the importance of FAO in proximal tubule function, these results led us to investigate the hypothesis that chronic exercise can protect kidneys from tubular injury. At 7 days post IRI, prior exercise training significantly reduced IRI-induced tubular damage areas and expression of tubular damage marker genes (KIM1, NGAL). At 28 days post IRI, prior exercise training significantly ameliorated IRI-induced fibrotic area and expression of fibrotic marker protein (αSMA). Among the FAO related proteins that were up-regulated by exercise in the MoTrPAC data, we found that prior-exercise training significantly ameliorated the IRI-induced reduction of peroxisomal FAO related proteins (e.g. Acox1, Ehhadh). Conclusion: Exercise training decreases IRI-induced kidney tubular damage, an affect associated with upregulation of FAO related proteins. Regular physical activity may provide a means to help prevent the severity of CKD. Funding: NIDDK Support - NIDDK Support, NIDDK Support, Private Foundation Support