Irisin alleviates hypertensive renal injury by suppressing communication between macrophages and tubular epithelial cells

BACKGROUND: Hypertensive renal injury (HRI) is characterized by renal inflammation and fibrosis. We investigated whether macrophage-tubular epithelial cell communication contributes to HRI and the renoprotective effects of irisin. METHODS: HRI was induced by unilateral nephrectomy, angiotensin II infusion, and a high-salt diet. FNDC5 knockout mice and recombinant irisin were used to assess endogenous and exogenous irisin, respectively. Single-cell RNA sequencing and CellChat characterized renal cell populations and predicted intercellular communication. Flow cytometry assessed macrophage Cd209a expression. A macrophage-tubular epithelial cell Transwell co-culture system, together with IL-1 receptor blockade and recombinant IL-1β stimulation, was used for functional validation. RESULTS: Irisin improved renal function and attenuated renal fibrosis and pEMT-related alterations without significantly reducing blood pressure, whereas FNDC5 deficiency aggravated renal fibrosis and macrophage accumulation. ScRNA-seq identified a Cd209a-high Macro-2 macrophage subset that expanded during HRI and was further increased by FNDC5 deficiency. CellChat predicted enhanced communication between Macro-2 macrophages and proximal tubular cells, with further enhancement following FNDC5 deficiency. In vitro, Ang II increased Cd209a expression and IL-1β secretion in RAW264.7 macrophages. Functional experiments suggested the involvement of IL-1β signaling in macrophage-induced pEMT-related alterations in tubular epithelial cells. Irisin pretreatment attenuated Ang II-induced macrophage inflammatory activation and reduced macrophage-induced pEMT-related and profibrotic alterations in TCMK-1 cells. CONCLUSIONS: Irisin protects against HRI by improving renal function and attenuating renal fibrosis without significantly affecting blood pressure. Macrophage-associated inflammatory responses and macrophage-tubular epithelial cell interactions may contribute to the renoprotective effects of irisin, supporting the FNDC5/irisin axis as a potential therapeutic target for HRI.