GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE312nnn/GSE312083/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE312083GEOGSEfalseFstl3 deletion unravels the role of activin signaling in regulating macrophage L-arginine metabolism and kidney injury [RNAseq_FA7d]Macrophages play a critical role in regulating kidney injury, inflammation and fibrosis. Arginase 1 (Arg1), a key enzyme in L-arginine metabolism, is predominantly expressed in macrophages in injured kidneys. Polyamines derived from L-arginine metabolism promote the resolution of tissue injury. Follistatin-like 3 (FSTL3) is an endogenous antagonist of activins. Circulating FSTL3 has been found to be associated with renal function in patients with chronic kidney injury (CKD), but the exact role of FSTL3 in the kidney remains to be identified. We now find that serum FSTL3 levels were elevated in AKI patients compared to healthy subjects. 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.2026/09/13GSE312083GSM9337516GSM9337515GSM9337514GSM9337513GSM9337519GSM9337518GSM9337517GSM9337523GSM9337512GSM9337522GSM9337521GSM933752034290312083Mus musculus