Il‐15 prevents renal fibrosis by inhibiting collagen synthesis: A new pathway in chronic kidney disease?

Abstract

Chronic kidney disease (CKD), secondary to renal fibrogenesis, is a public health burden. The activation of interstitial myofibroblasts and excessive production of extracellular matrix (ECM) proteins are major events leading to end‐stage kidney disease. Recently, interleukin‐15 (IL‐15) has been implicated in fibrosis protection in several organs, with little evidence in the kidney. Since endogenous IL‐15 expression decreased in nephrectomized human allografts evolving toward fibrosis and kidneys in the unilateral ureteral obstruction (UUO) model, we explored IL‐15’s renoprotective role by pharmologically delivering IL‐15 coupled or not with its soluble receptor IL‐15Rα. Despite the lack of effects on myofibroblast accumulation, both IL‐15 treatments prevented tubulointerstitial fibrosis (TIF) in UUO as characterized by reduced collagen and fibronectin deposition. Moreover, IL‐15 treatments inhibited collagen and fibronectin secretion by transforming growth factor‐β (TGF‐β)‐treated primary myofibroblast cultures, demonstrating that the antifibrotic effect of IL‐15 in UUO acts, in part, through a direct inhibition of ECM synthesis by myofibroblasts. In addition, IL‐15 treatments resulted in decreased expression of monocyte chemoattractant protein 1 (MCP‐1) and subsequent macrophage infiltration in UUO. Taken together, our study highlights a major role of IL‐15 on myofibroblasts and macrophages, two main effector cells in renal fibrosis, demonstrating that IL‐15 may represent a new therapeutic option for CKD.