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PAG1 aggravates diabetic nephropathy through TGF-β1/Smads-driven pyroptosis.
Xue Han1, Chen Xie1, Song Xue1
1Department of Nephrology and Endocrinology, Beijing Hospital of Integrated Traditional Chinese and Western Medicine, Beijing, China.
General Physiology and Biophysics
|June 17, 2026
Summary
Phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) promotes diabetic nephropathy (DN) by upregulating the TGF-β1/Smads pathway, leading to pyroptosis. Reducing PAG1 alleviates DN progression and inflammation.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) is a recognized biomarker for diabetic nephropathy (DN).
- The precise mechanisms by which PAG1 contributes to DN pathogenesis remain incompletely understood.
Purpose of the Study:
- To elucidate the functional role and molecular mechanisms of PAG1 in the development and progression of diabetic nephropathy.
- To investigate the impact of PAG1 on pyroptosis and the transforming growth factor-beta 1 (TGF-β1)/Smads signaling pathway in DN.
Main Methods:
- Bioinformatics analysis of PAG1 expression in DN patient samples.
- Validation of PAG1 expression in high glucose-treated HK-2 cells and db/db mouse models.
- Investigating the effects of PAG1 knockdown on DN progression, inflammation, pyroptosis, and TGF-β1/Smads pathway activation.
- Utilizing a TGF-β1/Smads pathway activator (SRI-011381) to further delineate PAG1's regulatory role.
Main Results:
- Elevated PAG1 expression was observed in DN samples and confirmed in cellular and animal models.
- PAG1 knockdown in db/db mice ameliorated DN, reduced inflammation, inhibited pyroptosis, and suppressed the TGF-β1/Smads pathway.
- In vitro, PAG1 silencing promoted cell proliferation, reduced apoptosis and fibrosis, and suppressed inflammatory and pyroptotic markers via the TGF-β1/Smads pathway.
- Intervention with SRI-011381 reversed the protective effects of PAG1 knockdown.
Conclusions:
- PAG1 exacerbates diabetic nephropathy by promoting pyroptosis through the upregulation of the TGF-β1/Smads pathway.
- Targeting PAG1 may represent a novel therapeutic strategy for managing diabetic nephropathy.
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