ArticleActa pharmacologica Sinica2025
PU.1/Spi1 exacerbates ischemia-reperfusion induced acute kidney injury via upregulating Gata2 and promoting fibroblast activation.
Article in Acta pharmacologica Sinica, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed.
- Transition from acute kidney injury to chronic kidney disease: molecular mechanisms and therapeutic interventions.Molecular biomedicine · 2026Review
- Spatiotemporal Control of Intercellular Crosstalk: A New Therapeutic Paradigm for Halting Acute Kidney Injury to Chronic Kidney Disease Transition.Biomolecules · 2026Review
- The response to kidney injury is epigenetically regulated through the activation of bivalent genes.American journal of physiology. Renal physiology · 2026Article
- In vitro models to mimic tumor endothelial cell-mediated immune cell reprogramming in lung adenocarcinoma.Journal of experimental & clinical cancer research : CR · 2025Article
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12 authors.
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Abstract
Previous studies on acute kidney injury (AKI) have predominantly focused on renal tubular cells, while the specific role of fibroblasts has been largely neglected. Recent evidence shows that PU.1/Spi1, a transcription factor, is an important modulator of fibroblast activation, whereas pharmacological and genetic silencing of PU.1/Spi1 disrupts the fibrotic network and reprograms activated fibroblasts into quiescent fibroblasts. In this study we investigated whether and how PU.1/Spi1 regulated renal fibroblast activation during AKI. An AKI model was established in male mice by clamping bilateral renal arteries for 30 min. Mice were sacrificed and blood and kidney samples were collected 48 h after the surgery. We showed that the expression level of PU.1/Spi1 was significantly upregulated in ischemia/reperfusion (I/R)-induced AKI and PU.1/Spi1 was specifically localized in fibroblasts. Meanwhile, we observed that a massive activation of fibroblasts occurred at the early stage of AKI. PU.1/Spi1 knockout significantly attenuated the activation of fibroblasts along with the decreased release of inflammatory factors and tubular injury. Bioinformatic analysis revealed that GATA binding protein 2 (Gata2), an evolutionarily conserved gene, might be a downstream target gene of PU.1/Spi1. In primary cultured mouse kidney fibroblasts subjected to hypoxia/reoxygenation (H/R), the expression levels of PU.1/Spi1, Gata2 and α-SMA were significantly upregulated. Activated fibroblasts exhibited elevated proliferative capacity, evidenced by upregulated proliferating cell nuclear antigen (PCNA) and cell cycle proteins such as cyclin B1 and cyclin D3. The secretion of inflammatory factors was increased in the activated fibroblasts. Conditioned medium from H/R-treated fibroblasts induced tubular cell injury and increased apoptosis. Using chromatin immunoprecipitation and promoter-luciferase assays, we demonstrated that PU.1/Spi1 was able to bind to the promoter region of Gata2 and enhanced its transcription. Our results show that interstitial fibroblasts are activated at the early stage of I/R-induced AKI and involved in renal injury. Upregulated PU.1/Spi1 stimulates fibroblast activation by upregulating its downstream gene Gata2. Inhibiting the activation of fibroblasts may have a beneficial effect on AKI.
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