The Wnt/β-catenin signaling pathway mediates renal fibrosis in glycogen storage disease type Ib nephropathy

Glycogen storage disease type Ib (GSD-Ib) results from a deficiency in the ubiquitously expressed glucose-6-phosphate transporter (G6PT), which partners with either the liver/kidney-specific glucose-6-phosphatase-α (G6Pase-α, G6PC1) or the ubiquitously expressed G6Pase-β (G6PC3) to produce glucose from G6P. A deficiency in G6Pase-α causes GSD-Ia. Since G6Pase-α is more active than G6Pase-β, glucose homeostasis is mainly maintained by the G6PT/G6Pase-α complex, and both GSD-Ia and GSD-Ib share metabolic defects and renal disease. GSD-Ia nephropathy is characterized by glomerulosclerosis and fibrosis, partly driven by Wnt/β-catenin signaling. In this study, we show that G6pt−/− (GSD-Ib) mice exhibit similar features, including Wnt/β-catenin-mediated fibrosis, but with significantly higher renal triglyceride levels compared to age-matched GSD-Ia mice during weeks 1 to 3 postnatal development, leading to an early onset of more severe kidney disease. G6Pase-β is highly expressed in the kidney but minimally in the liver, distinguishing the GSD-I subtypes. In GSD-Ia, G6PT/G6Pase-α activity is absent in both the liver and kidney, while G6PT/G6Pase-β is functionally active in the kidney. In GSD-Ib, both G6PT complexes are absent in the kidney and liver. Our results suggest that the less active G6PT/G6Pase-β complex plays a protective role in GSD-Ia kidney.