Faculty Collaboration Database

Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease. J Clin Invest 2013 Jul;123(7):3084-98

Date

06/20/2013

Pubmed ID

23778143

Pubmed Central ID

PMC4101988

DOI

10.1172/JCI64401

Scopus ID

2-s2.0-84879637271 (requires institutional sign-in at Scopus site)   118 Citations

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.

Author List

Zhou X, Fan LX, Sweeney WE Jr, Denu JM, Avner ED, Li X

Author

Ellis D. Avner MD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acetylation
Animals
Apoptosis
Carbazoles
Cell Proliferation
Cells, Cultured
Drug Evaluation, Preclinical
Epithelial Cells
Female
Gene Expression Regulation, Enzymologic
Kidney
Male
Mice
Mice, Knockout
Niacinamide
Phosphorylation
Polycystic Kidney, Autosomal Dominant
Protein Kinase C
Protein Processing, Post-Translational
Proto-Oncogene Proteins c-myc
Retinoblastoma Protein
Sirtuin 1
Tumor Necrosis Factor-alpha
Tumor Suppressor Protein p53