Six months of physical inactivity is insufficient to cause chronic kidney disease in C57BL/6J mice

Opurum, P. C.; Decker, S. T.; Stuart, D.; Peterlin, A. D.; Paula, V. L.; Siripoksup, P.; Drummond, M. J.; Sanchez, A.; Ramkumar, N.; Funai, K.

doi:10.1101/2024.08.29.610415

bioRxiv · 10.1101/2024.08.29.610415

Six months of physical inactivity is insufficient to cause chronic kidney disease in C57BL/6J mice

Opurum, P. C.·Decker, S. T.·Stuart, D.·Peterlin, A. D.·Paula, V. L.·Siripoksup, P.·Drummond, M. J.·Sanchez, A.·Ramkumar, N.·Funai, K.

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Abstract

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 employed a small mouse cage (SMC), a recently developed mouse model of sedentariness, to study its effect on kidney function. Wildtype C57BL/6J male mice were housed in sham or SMC housing for six months with HFD in room (22{degrees}C) or thermoneutral (30{degrees}C) conditions. Despite hyperinsulinemia induced by the SMC+HFD intervention, kidneys from these mice displayed normal glomerular filtration rate (GFR). However, the kidneys showed early signs of kidney injury, including increases in Col1a1 and NGAL 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.

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Opurum, P. C., Decker, S. T., Stuart, D., Peterlin, A. D., Paula, V. L., Siripoksup, P., Drummond, M. J., Sanchez, A., Ramkumar, N., Funai, K.. 2024-08-30. Six months of physical inactivity is insufficient to cause chronic kidney disease in C57BL/6J mice. https://doi.org/10.1101/2024.08.29.610415

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