Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease
Xia Zhou, … , Ellis D. Avner, Xiaogang Li
Xia Zhou, … , Ellis D. Avner, Xiaogang Li
Published June 17, 2013
Citation Information: J Clin Invest. 2013;123(7):3084-3098. https://doi.org/10.1172/JCI64401.
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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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Figure 9

Interaction of SIRT1 with Rb mediates Rb deacetylation and phosphorylation.

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Interaction of SIRT1 with Rb mediates Rb deacetylation and phosphorylati...
(A and B) Overexpression of WT SIRT1, but not deacetylase catalytically inactive mutant SIRT1 H355A, (A) decreased the level of acetylated Rb, as examined with anti–acetyl-α-lysine antibody after Rb was pulled down with anti-Rb antibody, and (B) increased the level of phospho-Rb, as examined by Western blot, in mouse IMCD3 cells transfected with WT SIRT1, mutant SIRT1 H355A, or empty vector for 48 hours. (C and D) Knockdown of SIRT1 with siRNA or inhibition of SIRT1 with nicotinamide increased the acetylation level of Rb in Pkd1-null MEK cells that were (C) transfected with SIRT1 siRNA for 48 hours or (D) treated with 10 mM nicotinamide for 24 hours. Rb acetylation was analyzed as above. (E and F) Knockdown of SIRT1 with siRNA or inhibition of SIRT1 with nicotinamide decreased Rb phosphorylation, but did not affect Rb expression, in WT MEK, Pkd1-null MEK, PH2, and PN24 cells that were (E) transfected with SIRT1 siRNA for 48 hours or (F) treated with 10 mM nicotinamide for 24 hours. *P 0.05; **P 0.01.