Epithelial and Interstitial Gli2 Activation Correlates With Renal Tubulointerstitial Fibrosis and Facilitates FoxM1-Associated Myofibroblast Phenotypic Transition.

Authors

Ziwei Yuan, Yining Sun, Linxin Kong, Shenlei Yu, Fan Zheng, Penghua Yan, Boyang Liu, Danni He, Yidan Zuo, Hong Lu, Yongheng Bai

Published in

FASEB journal : official publication of the Federation of American Societies for Experimental Biology. Volume 40. Issue 12. Pages e72057. Jun 30, 2026.

Abstract

Abnormal activation of Hedgehog signaling is involved in renal fibrogenesis, a key process in chronic kidney disease (CKD) progression. However, the isoform-specific roles of Gli transcription factors remain unclear. This study aimed to elucidate the contribution of Gli2 to renal fibrosis. Multiple murine models of renal fibrosis-unilateral ureteral obstruction, ischemia-reperfusion injury, and aristolochic acid nephropathy-were employed, alongside human CKD specimens. In vitro assays, including genetic silencing, overexpression, co-immunoprecipitation, immunofluorescence, promoter analysis, F-actin staining, and TGF-β/SB431542 intervention assays were used to evaluate Gli2 function and its interaction with FoxM1. This study identifies Gli2, but not Gli1 or Gli3, as the primary Hedgehog signaling mediator in fibrotic kidneys, showing its activation in both epithelial and interstitial compartments. TGF-β-induced Gli2 activation promoted fibrogenesis via tubular epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast differentiation (FMD), and cytoskeletal remodeling. FoxM1 is a potential dowgnstream candidate transcriptionally regulated by Gli2, with two conserved Gli-binding sites within its promoter. FoxM1 knockdown partially mitigated Gli2-driven fibrotic effects. Pharmacological Gli2 suppression with GANT61 alleviated fibrotic injury in the UUO mouse model. In conclusion, activated Gli2 is closely associated with renal tubulointerstitial fibrosis and may facilitate fibrogenesis in a FoxM1-relevant regulatory pattern. The TGF-β/Hedgehog/Gli2/FoxM1 axis represents a promising therapeutic target for combating progressive CKD.

PMID:
42295123
Bibliographic data and abstract were imported from PubMed on 15 Jun 2026.

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