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Exercise Induced Irisin Alleviates Type 1 Diabetic Nephropathy by Promoting Mitochondria Biogenesis and Function

Mitochondrial dysfunction is known to play an important role in the development and progression of chronic kidney disease. Improving mitochondrial homeostasis therefore has the potential to restore renal function in diabetic kidney disease. Exercise training was shown to be beneficial in improving skeletal muscle and cardiovascular system pathology by improving mitochondrial function, reduction of oxidative stress and metabolic reprogramming. Recent studies have shown that Irisin, a molecule secreted by the skeletal muscles during exercise protects the mitochondria from ischemia reperfusion injury in the lung and heart. In clinical studies, involving type 1 diabetes, high and low levels of Irisin has been reported however, its functional significance remains unclear. Exercise induces the expression of PGC‐1α, leading to the expression of the fibronectin type III domain containing 5 (FNDC5). Irisin derives from the proteolytic cleavage of the peptide FNDC5 by yet unknown enzymes. The purpose of our study was to investigate whether exercise induced Irisin improves mitochondrial biogenesis and function in type 1 diabetic nephropathy. C57BL/6‐Ins2Akita/J (Type 1 diabetes, Akita) and C57BL/6J (Wild type, WT) mice were subjected to 16‐week exercise regimen of 280m run on treadmill at speed of 7m/min for 5 days/week for 2 weeks and increased to 12m/min for the remaining 14 weeks. In vitro experiments were done in mouse glomerular endothelial cells (MGECs) treated with recombinant Irisin. In Akita and WT mice, exercise training improved renal vascularity, cortical blood flow and glomerular filtration rate compared to sedentary groups. Exercise upregulated Irisin expression in Akita and WT mice compared to sedentary mice but to a greater extent in WT mice. The protein and mRNA expression of PGC1α, PPARα and PPARγ were decreased in sedentary Akita mice and increased following exercise training suggesting induction of mitochondrial biogenesis. Sedentary Akita mice showed decreased expression of regulatory markers of mitochondrial DNA transcription, Nrf1, Nrf2, and Tfam and exercise normalized their expression. The expression of MnSOD and catalase were decreased in Akita mice suggesting impaired antioxidant defense and exercise restored their levels to normal. In conclusion, our results suggest that exercise induced Irisin protects the kidney in type 1 diabetes by restoring mitochondrial homeostasis.