Exercise Increases Resident Macrophage Abundance and Lipoxin A4 in Kidneys

Background: Exercise contributes to human health via benefits to several physiological systems; however, the mechanisms by which exercise impacts renal health remain poorly understood. Although exercise can be acutely stressful on the kidneys due to transient reductions in renal blood flow, studies show that moderate intensity exercise slows the age-related decline in kidney function. Additionally, exercise protects against AKI in both ischemic and nephrotoxic rodent models. We hypothesize that exercise triggers adaptative responses in kidney resident macrophages (KRMs) including production of specialized pro-resolving lipid mediators (SPMs), which preserves hemodynamic balance in the kidneys under stress. Methods: We performed a time course analysis of exercise-induced adaptations in the kidneys of 10 wk old C57BL/6J male mice. Mice were subjected to daily forced treadmill running at 70% capacity for 40 minutes for 1 or 2 wk. We also evaluated mice 24 h after a single bout of exhaustive exercise to discern acute responses from chronic adaptations. Sedentary mice were used as controls. We performed flow cytometry, targeted lipidomics, histopathology, and bulk mRNA sequencing to evaluate exercise-induced adaptations. Results: We found a significant increase in KRMs (CD45+CD11b+F4/80hi) after 2 wk of exercise compared to sedentary controls (p=0.0005). This increase was not present at either 24 h or 1 wk (Fig 1). We believe this was driven by expansion of KRMs rather than infiltration of monocyte derived macrophages as the population was primarily CX3CR1+CCR2-. Moreover, we found that 2 wk of exercise significantly increased renal lipoxin A4 (p=0.04), a vasoactive SPM that can be produced by macrophages and has been demonstrated to have renoprotective effects. Conclusion: Taken together, these data suggest that exercise alters the immune landscape of the kidney in a way that may preserve renal blood flow and reduce renal vascular congestion during kidney injury and recovery from insults. This study provides support for the utilization of exercise programs in the management of kidney disease.