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

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.

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.

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).

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.