Targeted deletion of kidney glucose-6 phosphatase leads to nephropathy.
Résumé
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.
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