Chronic Stress Induces Kidney Immunologic and Functional Changes

Background: Chronic stress (CS) due to prolonged exposure to negative life events has been linked to sustained systemic inflammation and cardiovascular diseases. We hypothesized that CS in mice would lead to kidney inflammation, which could in turn predispose to acute and chronic kidney diseases. Methods: Male C57BL/6J mice were subjected to two weeks of chronic social defeat stress by pair-housing with aggressive male CD-1 breeder mice. Control mice were pair-housed with non-aggressive conspecifics of the same strain in an identical environment, separated by a transparent divider to prevent physical interaction. Kidneys were evaluated by flow cytometric immunophenotyping, while multiplex cytokine assays were performed on kidney tissue and serum. Serum creatinine, cystatin C, and Neutrophil Gelatinase-Associated Lipocalin (NGAL) levels were measured. Results: Mice subjected to 2 weeks of CS had greater weight gain and worse fur quality than the control group. CS mice had elevated levels of serum cystatin C (515.9±16.9 vs. 456.6±14.8, P<0.05) and serum NGAL (833.1±282.4 vs. 90.6±5.57, P<0.0001). Kidney flow cytometry revealed a decrease in the proportion of CD4+ T cells (52.9±0.9% vs. 57.9±1.2%, P<0.01) and an increase in T helper 17 (Th17) (2.2±0.29% vs. 0.8±0.1%, P<0.001) and regulatory T cells (Tregs) (1.7±0.67% vs. 0.9±0.6%, P<0.05), leading to a higher Th17/Treg ratio (1.0±0.64 vs. 0.5±0.54, P <0.05). CS mice had increased serum TNF-α levels (8.5±1.2 vs. 3.2±1.3, P <0.01) and increased neutrophil percentage in kidneys (0.21±0.25% vs. 0.06±0.03%, P<0.05) compared to controls. Conclusion: Chronic stress induced an increase in kidney injury biomarkers and inflammatory responses with elevated kidney TNF-α, changes in Th17, Tregs, and neutrophil proportions. Future studies are required to assess mechanisms by which CS leads to kidney inflammation and its effects on susceptibility to AKI and CKD. Funding: NIDDK Support