Opurum Precious C, Decker Stephen T, Stuart Deborah, Peterlin Alek D, Paula Venisia L, Siripoksup Piyarat, Drummond Micah J, Sanchez Alejandro, Ramkumar Nirupama, Funai Katsuhiko
Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, Utah, United States.
Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah, United States.
Am J Physiol Renal Physiol. 2025 Jun 1;328(6):F850-F860. doi: 10.1152/ajprenal.00259.2024. Epub 2025 May 6.
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. 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.
慢性肾脏病（CKD）是一种以肾功能下降为特征的进行性疾病。肥胖和久坐行为会促进CKD的发展，但其发生机制尚不清楚。由于缺乏一种不依赖损伤、毒素或基因缺失来诱导肾功能降低的可靠小鼠CKD模型，这一知识空白进一步加剧。单纯高脂饮食（HFD）喂养不足以导致肾功能降低，直到生命后期才会出现。在此，我们使用了一种小型鼠笼（SMC），这是一种最近开发的模拟久坐行为的小鼠模型，来研究其对肾功能的影响。将野生型C57BL/6J雄性小鼠置于假手术或SMC饲养环境中6个月，同时在室温（22°C）或热中性（30°C）条件下给予HFD。尽管SMC + HFD干预诱导了高胰岛素血症，但这些小鼠的肾脏显示肾小球滤过率正常。然而，肾脏出现了早期肾损伤迹象，包括I型胶原蛋白和中性粒细胞明胶酶相关脂质运载蛋白转录本增加，以及组织学上的纤维化，主要发生在内髓质/乳头区域。高分辨率呼吸测定和荧光测定实验显示，呼吸、ATP合成或电子泄漏能力没有统计学上的显著变化。这些数据证实了在模拟人类CKD方面的技术挑战。它们进一步支持了肥胖和久坐的生活方式会使肾脏更易受损的观点，但CKD的发病可能还需要其他损伤因素。缺乏身体活动是慢性肾脏病的一个危险因素。我们实验室最近开发了一种新的缺乏身体活动的小鼠模型（小型鼠笼饲养），该模型更能重现久坐行为所伴随的代谢紊乱。在本文中，我们对小型鼠笼饲养条件下的肾功能和代谢参数进行了深入的表型分析。
