Impaired Glucose Metabolism, Primary Cilium Defects, and Kidney Cystogenesis in Glycogen Storage Disease Type Ia.

Abstract

Glycogen Storage Disease type Ia (GSDIa) is a rare metabolic disorder caused by mutations in the catalytic subunit of glucose-6 phosphatase (G6PC1). This leads to severe hypoglycemia and most young GSDIa patients develop CKD. The kidney pathology is characterized by the development of cysts, which typically occur at an advanced stage of CKD. To elucidate the molecular mechanisms responsible for cyst formation, we characterized renal metabolism, molecular pathways involved in cell proliferation and integrity primary cilium integrity, using mice in which G6pc1 was specifically deleted in the kidney from in utero stage. GSDIa mice exhibited renal fibrosis, high-inflammation, and cyst formation, leading to kidney dysfunction. In addition, the loss of G6PC1 led to the ectopic accumulation of glycogen and lipids in the kidneys, and a metabolic shift towards a Warburg-like metabolism. This metabolic adaptation was due to an excess of glucose-6 phosphate, which supports cell proliferation, driven by the MEK/ERK and AKT/mTOR pathways. Treatment of GSDIa mice with rapamycin, a target of the mTOR pathway, reduced cell proliferation and kidney damage. Our results also identified lipocalin 2 as a contributor to renal inflammation and an early biomarker of CKD progression in GSDIa mice. Its inactivation partially prevented kidney lesions in GSDIa. Importantly, primary cilium defects were observed in the kidneys of GSDIa mice. Metabolic adaptations due to glucose-6 phosphate accumulation in GSDIa renal tubules, towards a Warburg-like metabolism, appeared to promote cell proliferation and cyst formation in a similar manner to that observed in various cystic kidney diseases. This was associated with down-regulation of primary cilium gene expression and consequently, altered cilium morphology.