TY - JOUR
T1 - A tumor necrosis factor-α-mediated pathway promoting autosomal dominant polycystic kidney disease
AU - Li, Xiaogang
AU - Magenheimer, Brenda S.
AU - Xia, Sheng
AU - Johnson, Teri
AU - Wallace, Darren P.
AU - Calvet, James P.
AU - Li, Rong
PY - 2008/8
Y1 - 2008/8
N2 - Autosomal dominant polycystic kidney disease (ADPKD) is caused by heterozygous mutations in either PKD1 or PKD2, genes that encode polycystin-1 and polycystin-2, respectively. We show here that tumor necrosis factor-α (TNF-α), 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-α. Treatment of mouse embryonic kidney organ cultures with TNF-α resulted in formation of cysts, and this effect was exacerbated in the Pkd2+/- kidneys. TNF-α also stimulated cyst formation in vivo in Pkd2+/- mice. In contrast, treatment of Pkd2+/- mice with the TNF-α inhibitor etanercept prevented cyst formation. These data reveal a pathway connecting TNF-α signaling, polycystins and cystogenesis, the activation of which may reduce functional polycystin-2 below a critical threshold, precipitating the ADPKD cellular phenotype.
AB - Autosomal dominant polycystic kidney disease (ADPKD) is caused by heterozygous mutations in either PKD1 or PKD2, genes that encode polycystin-1 and polycystin-2, respectively. We show here that tumor necrosis factor-α (TNF-α), 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-α. Treatment of mouse embryonic kidney organ cultures with TNF-α resulted in formation of cysts, and this effect was exacerbated in the Pkd2+/- kidneys. TNF-α also stimulated cyst formation in vivo in Pkd2+/- mice. In contrast, treatment of Pkd2+/- mice with the TNF-α inhibitor etanercept prevented cyst formation. These data reveal a pathway connecting TNF-α 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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U2 - 10.1038/nm1783
DO - 10.1038/nm1783
M3 - Article
C2 - 18552856
AN - SCOPUS:49149111379
SN - 1078-8956
VL - 14
SP - 863
EP - 868
JO - Nature Medicine
JF - Nature Medicine
IS - 8
ER -