Abstract
An epidemic of chronic kidney disease of unknown etiology (Mesoamerican nephropathy) has emerged in hot regions of Central America. We have demonstrated that dehydration associated with recurrent heat exposure causes chronic kidney disease in animal models. However, the independent influence of core body temperature on kidney injury has not been explored. In the present study, we tested the hypothesis that kidney injury could be accelerated by increasing body temperature independent of external temperature. Wild-type mice were exposed to heat (39.5°C, 30 min, 2 times daily) with or without the mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) for 10 days. Core temperature, renal function, proteinuria, and renal histological and biochemical analyses were performed. Isolated mitochondria markers of oxidative stress were evaluated from kidney tissue. DNP increased body core temperature in response to heat by 1°C (42 vs. 41°C), which was transient. The mild increase in temperature correlated with worsening albuminuria (R = 0.715, P < 001), renal tubular injury, and interstitial infiltration of monocytes/macrophages. Tubular injury was marked in the outer medulla. This was associated with a reduction in kidney tissue ATP levels (nonheated control: 16.71 ± 1.33 nmol/mg and DNP + heat: 13.08 ± 1.12 nmol/mg, P < 0.01), reduced mitochondria, and evidence for mitochondrial oxidative stress. The results of the present study suggest that kidney injury in heat stress is markedly worsened by increasing core temperature. This is consistent with the hypothesis that clinical and subclinical heat stroke may play a role in Mesoamerican nephropathy.