IL‐15 Links Muscle–Kidney Crosstalk to Preserving Podocyte Mitochondrial Fusion and Attenuating Diabetic Nephropathy

OBJECTIVES: High glucose induces mitochondrial dysfunction in podocytes, contributing to the development of diabetic nephropathy (DN). There is increasing evidence that muscles play a protective role by secreting myokines into the kidneys. Here, we investigated how skeletal muscle influences podocyte health via muscle-kidney crosstalk. METHODS: To increase myokine release, we overexpressed PGC-1α specifically in skeletal muscle (mPGC-1α) and crossed these mice with db/m mice to generate diabetic mPGC-1α:db/db mice. In parallel, db/db mice were treated intraperitoneally with recombinant murine interleukin-15 (IL-15). Mechanistic studies were performed using isolated primary podocytes and cultured podocyte cell lines. RESULTS: Compared with db/db controls, mPGC-1α:db/db mice exhibited reduced urinary albumin excretion (p < 0.001), mesangial matrix expansion (p < 0.001), glomerular basement membrane thickening (p < 0.001) and urinary podocin excretion (p < 0.001), along with increased podocyte number (p < 0.001). Podocytes from mPGC-1α:db/db mice showed higher expression of Nephrin and COX IV (p < 0.05) and upregulation of multiple mitochondrial function-related genes, notably OPA1 (p < 0.05). Skeletal muscle from mPGC-1α:db/db mice displayed elevated IL-15 mRNA (p < 0.05) and protein (p < 0.01) levels, accompanied by increased plasma IL-15 concentrations (p < 0.05). IL-15 treatment enhanced podocyte mitochondrial respiration, including basal oxygen consumption rate (OCR, p < 0.05), ATP-coupled respiration (p < 0.05) and maximal respiration (p < 0.05). IL-15 preserved mitochondrial fusion under high-glucose conditions by increasing OPA1 expression (p < 0.05) and promoted OPA1 transcription via histone H3 acetylation at its promoter (p < 0.05). CONCLUSIONS: Skeletal muscle-derived IL-15 mediates renal protection by maintaining mitochondrial fusion in podocytes during DN progression. Targeting this pathway may offer a therapeutic strategy to preserve kidney function and slow progression to end-stage renal disease.