Abstract
Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in the enzyme glucose-6-phosphatase-α (G6Pase-α or G6PC) that is expressed primarily in the gluconeogenic organs, namely liver, kidney cortex, and intestine. Renal G6Pase-α 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/β-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/β-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/β-catenin signaling. We show that GSD-Ia mice have AKI that leads to activation of the Wnt/β-catenin/RAS axis. Renal fibrosis was demonstrated by increased renal levels of Snail1, α-smooth muscle actin (α-SMA), and extracellular matrix proteins, including collagen-Iα1 and collagen-IV. Treating GSD-Ia mice with a CBP/β-catenin inhibitor, ICG-001, significantly decreased nuclear translocated active β-catenin and reduced renal levels of renin, Snail1, α-SMA, and collagen-IV. The results suggest that inhibition of Wnt/β-catenin signaling may be a promising therapeutic strategy for GSD-Ia nephropathy.