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Letter
Nature Medicine 14, 863 - 868 (2008)
Published online: 15 June 2008 | doi:10.1038/nm1783
A tumor necrosis factor-
–mediated pathway promoting autosomal dominant polycystic kidney disease
Xiaogang Li1, Brenda S Magenheimer2, Sheng Xia1, Teri Johnson1, Darren P Wallace3, James P Calvet2 & Rong Li1,4
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is caused by heterozygous mutations in either PKD1 or PKD2, genes that encode polycystin-1 and polycystin-2, respectively1. We show here that tumor necrosis factor-
(TNF-), an inflammatory cytokine present in the cystic fluid of humans with ADPKD, disrupts the localization of polycystin-2 to the plasma membrane and primary cilia through a scaffold protein, FIP2, which is induced by TNF-. Treatment of mouse embryonic kidney organ cultures with TNF- resulted in formation of cysts, and this effect was exacerbated in the Pkd2+/- kidneys. TNF- also stimulated cyst formation in vivo in Pkd2+/- mice. In contrast, treatment of Pkd2+/- mice with the TNF- inhibitor etanercept prevented cyst formation. These data reveal a pathway connecting TNF- signaling, polycystins and cystogenesis, the activation of which may reduce functional polycystin-2 below a critical threshold, precipitating the ADPKD cellular phenotype.
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