Exercise sensitizes the pressure diuresis response: shifting immune landscapes underlie renal adaptations to exercise

Background: Exercise benefits several physiological systems to confer health; however, the mechanisms by which exercise impacts renal health remain poorly understood. Studies show moderate intensity exercise slows the age-related decline in kidney function. Additionally, exercise protects against AKI in several rodent models. We hypothesize that exercise triggers adaptative responses, which preserve hemodynamic balance in the kidneys under stress. Methods: We evaluated exercise-induced adaptations in 10–14-wk-old C57BL/6J male and female mice subjected to either 4 wk of voluntary wheel running or up to 2 wk of forced treadmill running (70% capacity for 40 min/d). Additionally, we evaluated endpoints 24 h after a single bout of exhaustive exercise to discern acute responses from chronic adaptations. We evaluated renal perfusion with contrast-enhanced ultrasound and assessed kidney function by measuring the ability to clear a volume load. Additionally, we performed flow cytometry, cytokine array, histopathology, and bulk mRNA sequencing to evaluate exercise-induced changes in the kidney. Results: We found a significant increase in the maximum steady state tissue contrast intensity in the kidneys of exercised male mice vs sedentary controls. Additionally, exercised male, but not female, mice excreted significantly more urine in the first hour after administration of a saline bolus. At the cellular level, we observed a significant increase in kidney resident macrophages (KRMs; CD45+CD11b+F4/80hi) after exercise training in male, but not female, mice. Because the macrophages were primarily CX3CR1+CCR2-, this suggests expansion of KRMs as the source of the increase. Lastly, bulk mRNA sequencing suggested exercise induces changes relating to water and sodium handling as well as angiogenesis and wound healing. Conclusions: These data suggest that exercise alters the immune landscape of the kidney, which may promote angiogenesis to increase renal microvasculature and improve sensitivity of the pressure diuresis response. Future studies will identify if macrophages cause the functional adaptations observed.