Targeted deletion of kidney glucose-6 phosphatase leads to nephropathy.
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, an effect resulting in marked nephromegaly and progressive glomerular hyperperfusion and hyperfiltration preceding the development of microalbuminuria and proteinuria. To better understand the end-stage nephropathy in glycogen storage disease type 1a, we generated a novel kidney-specific G6pc knockout (K-G6pc(-/-)) mouse, which exhibited normal life expectancy. After 6 months, 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 by transforming growth factor β1 signaling. The K-G6pc(-/-) mice developed microalbuminuria caused by the impairment of the glomerular filtration barrier. Thus, renal G6pc deficiency alone is sufficient to induce the development of the early-onset nephropathy observed in glycogen storage disease type 1a, independent of the liver disease. The K-G6pc(-/-) mouse model is a unique tool to decipher the molecular mechanisms underlying renal failure and to evaluate potential therapeutic strategies.
1] Institut National de la Santé et de la Recherche Médicale, U855, Lyon, France [2] Université de Lyon, Lyon, France [3] Université Lyon 1, Villeurbanne, France.
Julie
J
Clar
1] Institut National de la Santé et de la Recherche Médicale, U855, Lyon, France [2] Université de Lyon, Lyon, France [3] Université Lyon 1, Villeurbanne, France.
Blandine
B
Gri
Département de Pathologie, Hôpital Henri Mondor, Créteil, France.
Julien
J
Calderaro
Institut Clinique de la Souris, Phenomin IGBMC, CNRS, Université de Strasbourg INSERM, U964, Illkirch, France.
Marie-Christine
MC
Birling
Institut Clinique de la Souris, Phenomin IGBMC, CNRS, Université de Strasbourg INSERM, U964, Illkirch, France.
Yann
Y
Hérault
Universitair Medisch Centrum Groningen, Groningen, The Netherlands.
G Peter A
GP
Smit
1] Institut National de la Santé et de la Recherche Médicale, U855, Lyon, France [2] Université de Lyon, Lyon, France [3] Université Lyon 1, Villeurbanne, France.
Gilles
G
Mithieux
1] Institut National de la Santé et de la Recherche Médicale, U855, Lyon, France [2] Université de Lyon, Lyon, France [3] Université Lyon 1, Villeurbanne, France.
Fabienne
F
Rajas
D000419:Albuminuria / Q000209:etiology; D000818:Animals; D004108:Dilatation, Pathologic / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D060730:Glomerular Filtration Barrier / Q000503:physiopathology*; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D005953:Glycogen Storage Disease Type I / Q000150:complications / Q000235:genetics*; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology*; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000473:pathology; D012084:Renin-Angiotensin System; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D053773:Transforming Growth Factor beta1; D005952:Glucose-6-Phosphatase