IL-15 Signaling Pathways in the Kidney: Established Mechanisms and Hypotheses for Exercise-Associated Stress

Interleukin-15 (IL-15) is an immunoregulatory cytokine also recognized as a myokine, with experimentally demonstrated cytoprotective and metabolic effects. Renal tubular epithelial cells (TECs) and podocytes express components of the IL-15 receptor system, but the role of IL-15 in exercise-associated renal adaptation remains unclear. This review distinguishes evidence from renal experimental models from hypotheses regarding exercise-induced renoprotection. Cell-culture and preclinical studies support a role for IL-15 in promoting TEC survival and attenuating profibrotic responses. Separate studies in podocytes demonstrate a functional role for STAT5 in autophagy regulation and improvements in mitochondrial fusion and respiration in response to IL-15, with optic atrophy 1 (OPA1) implicated in the latter response. These findings do not establish a single integrated pathway or demonstrate that the same protective mechanisms operate during exercise. Strenuous exercise may transiently increase tubular stress- or injury-associated biomarkers; however, these increases do not necessarily indicate clinically significant acute kidney injury (AKI) and should be interpreted alongside measures of renal function and the clinical context. We outline a conceptual framework that distinguishes potentially protective responses in renal parenchymal cells from IL-15-dependent immune activation that may contribute to injury in selected disease settings. Cytokine availability, exposure duration, mode of presentation, receptor composition, and inflammatory context may influence these outcomes, but their roles in renal responses to exercise remain to be established. An increase in circulating IL-15 alone does not establish its skeletal muscle origin, delivery to the kidney, or biological activity in renal target cells. The key unresolved question is whether IL-15 produced by skeletal muscle in response to exercise reaches renal target cells in a biologically active form and confers measurable renoprotection.