Interleukin-6 modulates endoplasmic reticulum stress signaling and mitochondrial protein complexes in the kidney following acute exhaustive exercise

Abstract

Endoplasmic Reticulum (ER) homeostasis is closely regulated by an adaptive signaling network identified as the unfolded protein response (UPR), which is tightly related to the inflammatory pathway. However, physical exercise increases plasma concentrations of interleukin-6 (IL-6), which exhibits both pro- and anti-inflammatory properties that mediate ER function and mitochondrial metabolism, making its investigation relevant in physiological and pathological contexts. In kidney diseases, the IL-6 levels are effective in predicting mortality risk. To elucidate the relationship between exercise-induced IL-6 elevation, ER stress, and renal physiology, we explored the impact of an acute exhaustive exercise on the ER stress-related proteins and mitochondrial respiratory chain targets in the kidneys of IL-6 knockout (KO) mice. WT and IL-6 KO mice were divided into two subgroups for each phenotype: sedentary (Sed) and 1 h (after 1 h of acute exercise; Ex-1h). The kidneys were removed and prepared for histological, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and immunoblotting analysis. In summary, IL-6 KO mice had lower degranulated mast cells in the kidney. IL-6 KO mice exhibited reduced exercise performance. The Hspa5 mRNA levels were significantly increased in response to acute exhaustive exercise in both WT and KO groups, but Il-10 increased only in response to exercise in the KO group. Additionally, Ddit3 expression was significantly lower in IL-6 KO mice post-exercise, suggesting a blunted ER stress response without IL-6. At the protein levels, ATF6α expression was notably elevated in IL-6 KO mice following exercise. Regarding mitochondrial protein complexes, we observed lower protein levels of mitochondrial complex IV and CII in the WT Ex-1h group than in the WT Sed. At the same time, the absence of IL-6 did not seem to modify the expression of most mitochondrial complexes in response to acute exercise. Also, publicly available gene expression datasets in humans support our findings, indicating the upregulation of IL-6 signaling and heat shock proteins (HSPs), while decreasing mitochondrial respiratory complex mRNA levels in white blood cells of humans following acute exhaustive exercise. The findings indicate that IL-6 may modulate specific components of ER stress and cytokine responses in the kidney after acute exercise.