Macrophage Derived Galectin‐3 Promotes Renal Fibrosis and Diabetic Kidney Disease by Enhancing TGFβ1 Signaling

Abstract Over 30% of patients with type 2 diabetes develop diabetic kidney disease (DKD), which has emerged as a major contributor to end stage renal disease. Renal fibrosis represents the final pathological outcome of most chronic kidney disease, particularly DKD. This study demonstrates elevated levels of Galectin‐3 (Gal3), a lectin associated with inflammatory and fibrotic conditions, in the plasma and kidneys of DKD mice. Positive correlations between Gal3 expression and renal fibrosis are observed in both DKD patients and mice. Macrophage‐derived Gal3 is found to promote Transforming growth factor beta 1 (TGFβ1) signaling activation and renal fibrogenesis. Genetic ablation of Gal3 globally or specifically in macrophages, as well as pharmacological inhibition of Gal3, significantly attenuated kidney fibrosis in diabetic mice. Mechanistically, macrophage‐derived Gal3 interacted with TGFβ receptor2 (TGFBR2) and Pro‐TGFβ1, preventing TGFBR2 proteasomal degradation in fibroblasts and increasing TGFβ1 levels in the diabetic kidney. These events enhances TGFβ1 signaling activation and ultimately facilitated kidney fibrosis. The findings of this study suggest Gal3 as a potential therapeutic target for renal fibrosis and DKD.