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FoxM1 inhibition ameliorates renal interstitial fibrosis by decreasing extracellular matrix and
Yanhui Wang1, Qiaoling Zhou2, Rong Tang2
1Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008, China; Department of Geriatrics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China.
Abstract:
FoxM1 is a transcriptional regulator involved in tumor development, pulmonary fibrosis, and cardiac fibrosis. However, its role in renal interstitial fibrosis (RIF) has yet to be elucidated. We established a TGF-β1-stimulated human proximal tubular epithelial cell (HK-2) model in vitro and a unilateral ureteral obstruction (UUO)-induced rat RIF model in vivo. FoxM1 inhibition was achieved by siRNA interference in vitro and by injecting thiostrepton into UUO-induced RIF rats in vivo. The degree of renal damage and fibrosis were determined by histological assessment via hematoxylin and eosin (H&E) staining. Immunohistochemistry, western blots, and qPCR were used to determine the expression levels of FoxM1, Collagen I, E-cadherin, α-SMA, and Snail1. Our results showed that FoxM1 inhibition could ameliorate RIF and reduce the deposition of Collagen I. H&E staining revealed that renal structural damage, inflammatory cell infiltration, and ECM deposition were significantly attenuated by thiostrepton treatment in the UUO rats. Furthermore, FoxM1 downregulation significantly suppressed epithelial-to-mesenchymal transition, as evidenced by decreased protein and mRNA expression levels of α-SMA and Snail1 and a significant increase in protein and mRNA expression levels of E-cadherin. Collectively, these results suggested that FoxM1 inhibition could be a novel therapeutic strategy for the treatment of RIF.
Insights
Inhibiting the transcription factor FoxM1 can reduce renal interstitial fibrosis (RIF) and its associated kidney damage. This finding suggests FoxM1 inhibition as a potential new therapy for RIF.
Area of Science:
- Nephrology
- Molecular Biology
- Pathology
Background:
- FoxM1 is a known regulator in tumor development and fibrosis in lungs and heart.
- The specific role of FoxM1 in renal interstitial fibrosis (RIF) remains unclear.
- Understanding FoxM1's function in RIF is crucial for developing new treatments.
Purpose of the Study:
- To investigate the role of the transcription factor FoxM1 in renal interstitial fibrosis (RIF).
- To evaluate the therapeutic potential of inhibiting FoxM1 in RIF models.
Main Methods:
- Established in vitro (TGF-β1-stimulated HK-2 cells) and in vivo (UUO-induced rat) models of RIF.
- Utilized siRNA and thiostrepton to inhibit FoxM1 expression in vitro and in vivo, respectively.
- Assessed renal damage and fibrosis using histological staining (H&E) and measured protein/mRNA levels of key fibrotic and epithelial-mesenchymal transition markers (Collagen I, E-cadherin, α-SMA, Snail1) via immunohistochemistry, western blots, and qPCR.
Main Results:
- FoxM1 inhibition significantly ameliorated RIF and reduced Collagen I deposition.
- Histological analysis showed attenuated renal structural damage, inflammation, and extracellular matrix deposition in thiostrepton-treated rats.
- Downregulation of FoxM1 suppressed epithelial-to-mesenchymal transition, indicated by decreased α-SMA and Snail1, and increased E-cadherin expression.
Conclusions:
- FoxM1 plays a significant role in the development of RIF.
- Inhibiting FoxM1 demonstrates a therapeutic effect on RIF.
- Targeting FoxM1 presents a promising novel therapeutic strategy for treating renal interstitial fibrosis.
