Polycystic kidney disease


Autosomal dominant polycystic kidney disease (ADPKD) is an inherited systemic disorder caused by mutations in PKD1 or PKD2 that predominately affects the kidneys and is characterized by the formation of cysts in the kidneys and other organs. Xia Zhou and colleagues used a mouse model of ADPKD to explore the role of the protein sirtuin 1 in cyst formation. In the accompanying image, slices of kidney from (left to right) mice lacking sirtuin 1, ADPKD mice, mice lacking 1 copy of sirtuin 1 gene, and mice lacking both copies of the sirtuin 1 gene, were fixed and stained with hematoxylin to visualize the ADPKD-associated cysts. These data demonstrate that loss of both copies of sirtuin 1 reduces cyst formation in ADPKD. Interestingly, the activity of sirtuin 1 can be inhibited by treatment with vitamin B3, suggesting that this vitamin may also be beneficial in ADPKD.

Published June 17, 2013, by Jillian Hurst

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Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease
Xia Zhou, Lucy X. Fan, William E. Sweeney Jr., John M. Denu, Ellis D. Avner, Xiaogang Li
Xia Zhou, Lucy X. Fan, William E. Sweeney Jr., John M. Denu, Ellis D. Avner, Xiaogang Li
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Research Article

Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease

Abstract

Autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2 and is characterized by the development of multiple bilateral renal cysts that replace normal kidney tissue. Here, we used Pkd1 mutant mouse models to demonstrate that the nicotinamide adenine dinucleotide–dependent (NAD-dependent) protein deacetylase sirtuin 1 (SIRT1) is involved in the pathophysiology of ADPKD. SIRT1 was upregulated through c-MYC in embryonic and postnatal Pkd1-mutant mouse renal epithelial cells and tissues and could be induced by TNF-α, which is present in cyst fluid during cyst development. Double conditional knockouts of Pkd1 and Sirt1 demonstrated delayed renal cyst formation in postnatal mouse kidneys compared with mice with single conditional knockout of Pkd1. Furthermore, treatment with a pan-sirtuin inhibitor (nicotinamide) or a SIRT1-specific inhibitor (EX-527) delayed cyst growth in Pkd1 knockout mouse embryonic kidneys, Pkd1 conditional knockout postnatal kidneys, and Pkd1 hypomorphic kidneys. Increased SIRT1 expression in Pkd1 mutant renal epithelial cells regulated cystic epithelial cell proliferation through deacetylation and phosphorylation of Rb and regulated cystic epithelial cell death through deacetylation of p53. This newly identified role of SIRT1 signaling in cystic renal epithelial cells provides the opportunity to develop unique therapeutic strategies for ADPKD.

Authors

Xia Zhou, Lucy X. Fan, William E. Sweeney Jr., John M. Denu, Ellis D. Avner, Xiaogang Li

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