Persistent Activation of Renal Autophagy Contributes to Nephropathy in Murine Glycogen Storage Disease Type Ia.

Abstract

Kidney disease in glycogen storage disease type Ia (GSD-Ia), deficient in glucose-6-phosphatase-α (G6Pase-α), is associated with acute kidney injury (AKI) and renal fibrosis. During AKI, autophagy is typically activated to eliminate protein aggregates and damaged organelles; however, sustained autophagy can contribute to maladaptive repair and fibrosis. Using a GSD-Ia mouse model, we demonstrate that renal G6Pase-α deficiency results in heightened autophagy activation, as indicated by increased expression of multiple autophagy-related components and enhanced autophagic flux. Notably, both positive regulators of autophagy, including sirtuin-1, forkhead box O3a, and AMP-activated protein kinase, as well as the key negative regulator, mammalian target of rapamycin (mTOR), were concurrently activated in the kidneys of GSD-Ia mice. Previous studies have shown that in response to AKI, renal levels of cyclin G1 (CG1) and cyclin-dependent kinase 5 (CDK5) increase, promoting maladaptive dedifferentiation, G2/M cell cycle arrest in proximal tubular epithelial cells, and the formation of a TOR-autophagy spatial coupling compartment. This sequence of events contributes to profibrotic factor production and accelerates the progression of kidney disease. In this study, we observed a significant elevation of renal CG1 and CDK5 in GSD-Ia mice with enhanced autophagy, suggesting a potential mechanistic link to the development of renal fibrosis in GSD-Ia. A deeper understanding of these pathways may facilitate the development of targeted therapies for GSD-Ia nephropathy.