A model of recurrent heat stress that causes kidney injury in mice

Chronic kidney disease (CKD) of nontraditional origin disproportionately affects outdoor workers exposed to high environmental temperatures. Recurrent heat stress with dehydration (rHS) is a major contributor to kidney injury; however, the underlying mechanisms remain poorly understood. We aimed to develop and validate a reproducible murine model of rHS-induced CKD in male and female mice. Young C57BL/6J mice were assigned to ambient temperature control (AT), a single heat stress exposure (HS1), or recurrent heat stress (rHS; 9 exposures over 3 wk). Each exposure consisted of 3 h at 40°C and 50% relative humidity without access to food or water, resulting in dehydration with an acute 4-6.5% reduction in body mass. One month after protocol initiation, male rHS mice exhibited a significant decline in glomerular filtration rate (ΔGFR = -56.5 ± 87 μL/min), elevated plasma creatinine (0.07 ± 0.01 vs. 0.11 ± 0.02 mg/dL, P < 0.001), and increased albuminuria (65 ± 21 vs. 198 ± 92 μg/mg creatinine, P < 0.001). Female rHS mice also exhibited increased plasma creatinine (0.08 ± 0.004 vs. 0.11 ± 0.02 mg/dL, P = 0.002) but demonstrated a smaller decline in GFR and minimal albuminuria. Histological analysis revealed tubular injury, interstitial fibrosis, and glomerulosclerosis in both sexes. Compared with AT control mice, renal PECAM1-positive area was reduced by 42.5% in males and 31.6% in females, indicating microvascular loss, and was accompanied by increased renal macrophage and T-cell accumulation. These findings establish a murine model of kidney injury induced by recurrent heat stress-mediated dehydration in both sexes, although young female mice exhibited partial protection from adverse renal effects.NEW & NOTEWORTHY Here we present a recurrent heat stress model that produces consistent increases in core temperature and dehydration with each event, leading to kidney injury in male and female mice. This robust and reproducible model demonstrates that repeated heat exposure drives sustained kidney injury, inflammation, and functional decline. It offers a valuable platform for mechanistic investigation and therapeutic development relevant to CKD of nontraditional origin.