| First Author | Lee C | Year | 2024 |
| Journal | Biochim Biophys Acta Mol Basis Dis | Volume | 1870 |
| Issue | 1 | Pages | 166874 |
| PubMed ID | 37666439 | Mgi Jnum | J:357685 |
| Mgi Id | MGI:7528395 | Doi | 10.1016/j.bbadis.2023.166874 |
| Citation | Lee C, et al. (2023) Inhibition of Wnt/beta-catenin signaling reduces renal fibrosis in murine glycogen storage disease type Ia. Biochim Biophys Acta Mol Basis Dis 1870(1):166874 |
| abstractText | Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in the enzyme glucose-6-phosphatase-alpha (G6Pase-alpha or G6PC) that is expressed primarily in the gluconeogenic organs, namely liver, kidney cortex, and intestine. Renal G6Pase-alpha deficiency in GSD-Ia is characterized by impaired gluconeogenesis, nephromegaly due to elevated glycogen accumulation, and nephropathy caused, in part, by renal fibrosis, mediated by activation of the renin-angiotensin system (RAS). The Wnt/beta-catenin signaling regulates the expression of a variety of downstream mediators implicated in renal fibrosis, including multiple genes in the RAS. Sustained activation of Wnt/beta-catenin signaling is associated with the development and progression of renal fibrotic lesions that can lead to chronic kidney disease. In this study, we examined the molecular mechanism underlying GSD-Ia nephropathy. Damage to the kidney proximal tubules is known to trigger acute kidney injury (AKI) that can, in turn, activate Wnt/beta-catenin signaling. We show that GSD-Ia mice have AKI that leads to activation of the Wnt/beta-catenin/RAS axis. Renal fibrosis was demonstrated by increased renal levels of Snail1, alpha-smooth muscle actin (alpha-SMA), and extracellular matrix proteins, including collagen-Ialpha1 and collagen-IV. Treating GSD-Ia mice with a CBP/beta-catenin inhibitor, ICG-001, significantly decreased nuclear translocated active beta-catenin and reduced renal levels of renin, Snail1, alpha-SMA, and collagen-IV. The results suggest that inhibition of Wnt/beta-catenin signaling may be a promising therapeutic strategy for GSD-Ia nephropathy. |
