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-1&#x3b1; specifically in skeletal muscle (mPGC-1&#x3b1;) and crossed these mice with db/m mice to generate diabetic mPGC-1&#x3b1;: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-1&#x3b1;:db/db mice exhibited reduced urinary albumin excretion (p&#x2009;<&#x2009;0.001), mesangial matrix expansion (p&#x2009;<&#x2009;0.001), glomerular basement membrane thickening (p&#x2009;<&#x2009;0.001) and urinary podocin excretion (p&#x2009;<&#x2009;0.001), along with increased podocyte number (p&#x2009;<&#x2009;0.001). Podocytes from mPGC-1&#x3b1;:db/db mice showed higher expression of Nephrin and COX IV (p&#x2009;<&#x2009;0.05) and upregulation of multiple mitochondrial function-related genes, notably OPA1 (p&#x2009;<&#x2009;0.05). Skeletal muscle from mPGC-1&#x3b1;:db/db mice displayed elevated IL-15 mRNA (p&#x2009;<&#x2009;0.05) and protein (p&#x2009;<&#x2009;0.01) levels, accompanied by increased plasma IL-15 concentrations (p&#x2009;<&#x2009;0.05). IL-15 treatment enhanced podocyte mitochondrial respiration, including basal oxygen consumption rate (OCR, p&#x2009;<&#x2009;0.05), ATP-coupled respiration (p&#x2009;<&#x2009;0.05) and maximal respiration (p&#x2009;<&#x2009;0.05). IL-15 preserved mitochondrial fusion under high-glucose conditions by increasing OPA1 expression (p&#x2009;<&#x2009;0.05) and promoted OPA1 transcription via histone H3 acetylation at its promoter (p&#x2009;<&#x2009;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.