Six Months of High-Fat Diet and Physical Inactivity in Thermoneutrality Are Insufficient to Cause CKD in Mice

Background: Chronic kidney disease (CKD) is a progressive disorder marked by a decline in kidney function. The process by which obesity and sedentary behavior contribute to the development of CKD is poorly understood. Studies suggest a decline in mitochondrial function likely contributes to the pathogenesis of CKD, but the detailed mechanisms remain unclear. This knowledge gap is contributed to by a lack of a murine CKD model that does not rely on injury, toxin, or gene deletion to induce reduced kidney function. Methods: Here, we employed a recently published model of sedentariness developed in our lab, which phenocopies many of the systemic metabolic adaptations that occur in human sedentary behavior. Wildtype C57BL/6J male mice housed under ambient (22°C) or thermoneutral conditions (29°C) were fed standard chow or Western high-fat diet (HFD) with or without small mice cage (SMC) intervention for 6 months. Results: However, while HFD or SMC tended to increase the glomerular filtration rate (GFR), these interventions were insufficient to cause CKD. Histological and gene expression data suggested a potential early onset of fibrosis programming, but the magnitudes of these changes were minor. High-resolution respirometry and fluorometry experiments showed increases in mitochondrial respiration and ATP synthesis capacities, also likely demonstrating early adaptive responses to heightened kidney burden. Conclusion: Given the long duration of the intervention, these data reinforce the technical challenge associated with modeling CKD in mice. They also suggest that metabolic pressures caused by obesogenic diet and/or sedentariness may be insufficient to robustly negatively influence kidney function. Funding: NIDDK Support