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

ABSTRACT 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  p  p  p  p  p  p  p  p  p  p  p  p  p  p   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.