ArticleThe Journal of clinical investigation2015
Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis.
Article in The Journal of clinical investigation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers.
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Who cites it
87 citing papers in PubMed, 165 citations in OpenAlex.
- Mechanisms of regeneration and maladaptive repair in acute kidney injury.Nature reviews. Nephrology · 2026Review
- The inflammatory/fibrotic axis across organs: myelofibrosis as a model of reversibility.JCI insight · 2026Review
- Shared mechanisms of organ fibrosis.JCI insight · 2026Review
- SUN2 mediates epigenetic remodeling to drive mechanotransduction during skin fibrosis.bioRxiv : the preprint server for biology · 2026Article
- Pirfenidone attenuates urethral stricture after injury by inhibiting Gli2 mediated HAS2 expression in fibroblasts.Journal of molecular histology · 2026Article
- Renal allograft interstitial fibrosis: multicellular interactions and therapeutic strategies.Frontiers in immunology · 2026Review
- Protecting kidney function: from mechanisms to therapeutic targets and traditional Chinese medicine.Renal failure · 2025Review
- Integrative analysis based on CRISPR screen identifies apilimod as a potential therapeutic agent for cisplatin-induced acute kidney injury treatment.Science China. Life sciences · 2025Article
- Identification of Ferroptosis-related Genes for Diabetic Nephropathy by Bioinformatics and Experimental Validation.Current pharmaceutical design · 2025Article
- Hedgehog Signaling Pathway in Fibrosis and Targeted Therapies.Biomolecules · 2024Review
- Retinoic acid enhances ovarian steroidogenesis by regulating granulosa cell proliferation and MESP2/STAR/CYP11A1 pathway.Journal of advanced research · 2024Article
- CXCL12+ dermal fibroblasts promote neutrophil recruitment and host defense by recognition of IL-17.The Journal of experimental medicine · 2024Article
- Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms.Cell reports · 2024Article
- Kidney Injury: Focus on Molecular Signaling Pathways.Current medicinal chemistry · 2024Review
- Cep120 is essential for kidney stromal progenitor cell growth and differentiation.EMBO reports · 2024Article
- Role of perivascular cells in kidney homeostasis, inflammation, repair and fibrosis.Nature reviews. Nephrology · 2023Review
- Plk1 promotes renal tubulointerstitial fibrosis by targeting autophagy/lysosome axis.Cell death & disease · 2023Article
- Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies.Signal transduction and targeted therapy · 2023Review
- Review
- Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis.Science translational medicine · 2023Article
27 more citing papers are in PubMed but not listed here.
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13 authors at 2 institutions in 2 countries.
Funding
Abstract
Chronic kidney disease is characterized by interstitial fibrosis and proliferation of scar-secreting myofibroblasts, ultimately leading to end-stage renal disease. The hedgehog (Hh) pathway transcriptional effectors GLI1 and GLI2 are expressed in myofibroblast progenitors; however, the role of these effectors during fibrogenesis is poorly understood. Here, we demonstrated that GLI2, but not GLI1, drives myofibroblast cell-cycle progression in cultured mesenchymal stem cell-like progenitors. In animals exposed to unilateral ureteral obstruction, Hh pathway suppression by expression of the GLI3 repressor in GLI1+ myofibroblast progenitors limited kidney fibrosis. Myofibroblast-specific deletion of Gli2, but not Gli1, also limited kidney fibrosis, and induction of myofibroblast-specific cell-cycle arrest mediated this inhibition. Pharmacologic targeting of this pathway with darinaparsin, an arsenical in clinical trials, reduced fibrosis through reduction of GLI2 protein levels and subsequent cell-cycle arrest in myofibroblasts. GLI2 overexpression rescued the cell-cycle effect of darinaparsin in vitro. While darinaparsin ameliorated fibrosis in WT and Gli1-KO mice, it was not effective in conditional Gli2-KO mice, supporting GLI2 as a direct darinaparsin target. The GLI inhibitor GANT61 also reduced fibrosis in mice. Finally, GLI1 and GLI2 were upregulated in the kidneys of patients with high-grade fibrosis. Together, these data indicate that GLI inhibition has potential as a therapeutic strategy to limit myofibroblast proliferation in kidney fibrosis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.