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Kidney Int. 2014 Oct;86(4):747-56. doi: 10.1038/ki.2014.102. Epub 2014 Apr 9.

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

Author information

1
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.
2
Département de Pathologie, Hôpital Henri Mondor, Créteil, France.
3
Institut Clinique de la Souris, Phenomin IGBMC, CNRS, Université de Strasbourg INSERM, U964, Illkirch, France.
4
Universitair Medisch Centrum Groningen, Groningen, The Netherlands.

Abstract

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.

PMID:
24717294
PMCID:
PMC5678048
DOI:
10.1038/ki.2014.102
[Indexed for MEDLINE]
Free PMC Article

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