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.
Lee et al. (Mon,) studied this question.
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