Glycogen Storage Disorder Type la (GSD1a), also known as von Gierkes disease, is the most common Glycogen Storage Disorder.It is caused by loss of function of Glucose-6-Phosphatase (G6PC), the enzyme responsible for producing intracellular free glucose from Glucose-6-Phosphate.G6PC is expressed in the liver and kidney, and is the terminal step in gluconeogenesis.Patients with this disorder often suffer from hypoglycemia, non-alcoholic fatty liver disease, and chronic glomerular damage that can lead to renal failure;however, the etiology of the renal dysfunction is not known.As glycogen and lipids accumulate in the kidneys of patients with GSD1a, and acumulation of these metabolites is often associated with impaired autophagy, we examined whether autophagy is impaired in kidneys in G6PC knockout mice.Interestingly, we observed that renal LC3B-Ⅱ was decreased when compared to wild type mice,along with increased activation of the anti-autophagic mTOR and inhibition of the proautophagic AMPK pathways, implying a decrease in autophagy.More striking, we observed that the expression of endoplasmic reticulum (ER) stress markers was increased in G6PC knockout mice.We then treated these mice with the autophagy inducer, rapamycin, for 10 days,and observed an increase in autophagy that was coupled with a reduction in ER stress markers in the kidneys.Taken together, these results suggest that decreased autophagy and increased ER stress may play significant roles in the development of GSD1a renal insufficiency, a condition for which there currently is no approved treatment.Since restoring renal autophagy led to reduced ER stress in G6PC knockout mice, it is possible that induction of autophagy by rapamycin or other inducers of autophagy may be novel therapeutic agents to prevent or treat the renal complications of GSD1a.