Exercise Training Drives Proteomic Changes in Male Kidneys and Protects from High-Fat Diet-Induced Kidney Injury: A MoTrPAC Study

Background: While regular exercise training is broadly recognized to promote human metabolic health, little is known about the potential role of exercise in preventing kidney disease. Moreover, there have been few studies that have investigated the mechanisms by which exercise may provide protection from kidney disease. Methods: To elucidate the effects of exercise training on kidney, we first analyzed the kidney proteomics data from MoTrPAC, the NIH-funded Molecular Transducers of Physical Activity Consortium that investigates the multi-tissue molecular responses to 1, 2, 4, and 8 weeks of treadmill exercise training in rats. Second, we used a murine high-fat diet (HFD)-induced kidney injury model to determine if there are protective effects of exercise training. Male DBA2J mice were housed in cages with or without running wheels and fed a normal chow diet or HFD for four weeks. Results: We identified 2,161 differentially expressed proteins (DEPs) across four time points of exercise training in male rat kidneys. The 8-week training group had the highest number of DEPs, including 512 up-regulated proteins (p < 0.05). Pathway analysis revealed that fatty acid and peroxisomal β-oxidation-related pathways were consistently upregulated across all four training time points. For the HFD-induced kidney injury study, exercise training significantly reduced HFD-induced increases in body weight and adipose tissue weight, and had a tendency to decrease fasting glucose and serum creatinine (p < 0.09). Strikingly, exercise training significantly ameliorated HFD-induced tubular vacuolization, a hallmark of tubular injury and lipid accumulation. Based on the results from the MoTrPAC study, we focused on ACOX1 and PECR, key peroxisomal enzymes in fatty acid β-oxidation, which have been reported to be downregulated in injured kidneys. We found that exercise training significantly ameliorated the HFD-induced reductions in ACOX1 protein expression and significantly up-regulated PECR protein expression. Conclusion: In summary, we discovered that exercise training remarkably alters the kidney proteome, promoting key adaptations that improve metabolic dysfunction-associated kidney disease. These findings advance our molecular understanding and suggest that regular exercise can help mitigate CKD severity. Funding: NIDDK Support - NIDDK Support, NIDDK Support, Private Foundation Support