Twist1 regulates macrophage plasticity to promote renal fibrosis through galectin-3

Renal interstitial fibrosis is the pathological basis of end-stage renal disease, in which the heterogeneity of macrophages in renal microenvironment plays an important role. However, the molecular mechanisms of macrophage plasticity during renal fibrosis progression remain unclear. In this study, we found for the first time that increased expression of Twist1 in macrophages was significantly associated with the severity of renal fibrosis in IgA nephropathy patients and mice with unilateral ureteral obstruction (UUO). Ablation of Twist1 in macrophages markedly alleviated renal tubular injury and renal fibrosis in UUO mice, accompanied by a lower extent of macrophage infiltration and M2 polarization in the kidney. The knockdown of Twist1 inhibited the chemotaxis and migration of macrophages, at least partially, through the CCL2/CCR2 axis. Twist1 downregulation inhibited M2 macrophage polarization and reduced the secretion of the profibrotic factors Arg-1, MR (CD206), IL-10, and TGF-beta. Galectin-3 was decreased in the macrophages of the conditional Twist1-deficient mice, and Twist1 was shown to directly activate galectin-3 transcription. Up-regulation of galectin-3 recovered Twist1-mediated M2 macrophage polarization. In conclusion, Twist1/galectin-3 signaling regulates macrophage plasticity (M2 phenotype) and promotes renal fibrosis. This study could suggest new strategies for delaying kidney fibrosis in patients with chronic kidney disease.

Automated summary

This study reveals a significant association between Twist1 expression in macrophages and the severity of renal fibrosis in IgA nephropathy patients and mice with unilateral ureteral obstruction. Twist1 ablation in macrophages alleviates renal tubular injury and fibrosis, accompanied by reduced macrophage infiltration and M2 polarization in the kidney. Twist1 downregulation inhibits macrophage chemotaxis and migration, at least partially through the CCL2/CCR2 axis. This study highlights the regulation of macrophage plasticity through Twist1/galectin-3 signaling and its potential as a new strategy for delaying kidney fibrosis in chronic kidney disease patients.