Combined sedentarism and high-fat diet induce early signs of kidney injury in C57BL/6J mice

Chronic kidney disease (CKD) is a progressive disorder marked by a decline in kidney function. Obesity and sedentary behavior contribute to the development of CKD, though mechanisms by which this occurs are poorly understood. This knowledge gap is worsened by the lack of a reliable murine CKD model that does not rely on injury, toxin, or gene deletion to induce a reduction in kidney function. High-fat diet (HFD) feeding alone is insufficient to cause reduced kidney function until later in life. Here, we used a small mouse cage (SMC), a recently developed mouse model of sedentariness, to study its effect on kidney function. Wild-type C57BL/6J male mice were housed in sham or SMC housing for 6 mo with HFD in room (22°C) or thermoneutral (30°C) conditions. Despite hyperinsulinemia induced by the SMC + HFD intervention, kidneys from these mice displayed normal glomerular filtration rate. However, the kidneys showed early signs of kidney injury, including increases in collagen I and neutrophil gelatinase-associated lipocalin transcripts, as well as fibrosis by histology, primarily in the inner medullary/papilla region. High-resolution respirometry and fluorometry experiments showed no statistically significant changes in the capacities for respiration, ATP synthesis, or electron leak. These data confirm the technical challenge in modeling human CKD. They further support the notion that obesity and a sedentary lifestyle make the kidneys more vulnerable, but additional insults are likely required for the pathogenesis of CKD.<b>NEW & NOTEWORTHY</b> Physical inactivity is a risk factor for chronic kidney disease. Our laboratory recently developed a new mouse model of physical inactivity (small mouse cage housing) that more closely recapitulates the metabolic disturbances that occur with sedentary behavior. In this paper, we performed an in-depth phenotyping of kidney function and metabolic parameters in response to small mouse cage housing.