Renal failure is a major complication that arises with aging in glycogen storage disease type 1a and type 1b patients. In the kidneys, glucose-6 phosphatase catalytic subunit (encoded by G6pc) deficiency leads to the accumulation of glycogen; this effect results in marked nephromegaly and progressive glomerular hyperperfusion and hyperfiltration, which precede the development of microalbuminuria and proteinuria. To better understand the end-stage nephropathy in glycogen storage disease type 1a, we generated a novel kidneyspecific G6pc knock-out (K-G6pc-/-) mouse, which exhibited normal life expectancy. After 6 months of G6pc deficiency, K-G6pc-/- mice showed glycogen overload leading to nephromegaly and tubular dilation. Moreover, renal accumulation of lipids due to activation of de novo lipogenesis was observed. This led to the activation of the renin-angiotensin system and the development of epithelial-mesenchymal transition process and podocyte injury via transforming growth factor β1 signaling. Thus, K-G6pc-/- mice developed microalbuminuria caused by the impairment of glomerular filtration barrier. In conclusion, renal G6pc deficiency alone is sufficient to induce the development of the early onset nephropathy observed in glycogen storage disease type 1a, independently of the liver disease. K-G6pc-/- mouse model is a unique tool to decipher the molecular mechanisms underlying renal failure and to evaluate potential therapeutic strategies.