Fstl3 deletion unravels the role of activin signaling in regulating macrophage L-arginine metabolism and kidney injury [RNAseq_FA7d]

Deletion of Fstl3 in mice alleviated renal injury and fibrosis induced by folic acid (FA) or cisplatin, which were associated with increased macrophage Smad3 phosphorylation and Arg1 expression. RNA-seq analysis revealed that arginine metabolism was highly enriched in the injured kidneys of Fstl3 KO mice or in bone marrow-derived macrophages (BMDMs) treated with activin A and IL-4. In vitro, activin A synergized with the Th2 cytokines, IL-4 and IL-13, to stimulate the expression of Arg1 as well as Slc7a2 (Cat2) and Gatm, two other key L-arginine metabolism genes, in macrophages, thereby exhausting extracellular L-arginine and enhancing the production of polyamines.

Following FA treatment, Fstl3 KO mice exhibited reduced tubular cell apoptosis, increased tubular cell proliferation, and diminished T lymphocyte infiltration in the kidney. Taken together, our results uncover a previously unrecognized role of activin signaling in regulating L-arginine metabolism. Fstl3 deletion activates L-arginine metabolism in macrophages, thereby facilitating the resolution of kidney injury.