Abstract
Autosomal recessive polycystic kidney disease (ARPKD) is an important childhood nephropathy, occurring 1 in 20,000 live births. The major clinical phenotypes are expressed in the kidney with dilatation of the collecting ducts, systemic hypertension, and progressive renal insufficiency, and in the liver with biliary dysgenesis, portal tract fibrosis, and portal hypertension. The systemic hypertension has been attributed to enhanced distal sodium reabsorption in the kidney, the structural defects have been ascribed to altered cellular morphology, and fibrosis to increased TGF-β signaling in the kidney and biliary tract, respectively. The pathogenic mechanisms underlying these abnormalities have not been determined. In the current report, we find that disrupting PKHD1 results in altered sub-cellular localization and function of the C2-WWW-HECT domain E3 family of ligases regulating these processes. We also demonstrate altered activity of RhoA and increased TGF-β signaling and ENaC activity. Linking these phenomena, we found that vesicles containing the PKHD1/Pkhd1 gene product, FPC, also contain the NEDD4 ubiquitin ligase interacting protein, NDFIP2, which interacts with multiple members of the C2-WWW-HECT domain E3 family of ligases. Our results provide a mechanistic explanation for both the cellular effects and in vivo phenotypic abnormalities in mice and humans that result from Pkhd1/PKHD1 mutation.
Highlights
Autosomal recessive polycystic kidney disease (ARPKD) is an important childhood nephropathy, occurring 1 in 20,000 live births
Liver disease is a universal feature of this disorder, characterized by a ductal plate malformation (DPM) that leads to increased number of irregularly shaped and dilated biliary ductules, with variable degrees of associated fibrosis
We evaluated the expression of RhoA, Rac[1] and Cdc[42] and found that RhoA expression was consistently lower in the PKHD1+ cell lines than in controls while levels of Rac[1] and Cdc[42] did not differ (Fig. 1a)
Summary
Autosomal recessive polycystic kidney disease (ARPKD) is an important childhood nephropathy, occurring 1 in 20,000 live births. We demonstrate altered activity of RhoA and increased TGF-β signaling and ENaC activity Linking these phenomena, we found that vesicles containing the PKHD1/Pkhd[1] gene product, FPC, contain the NEDD4 ubiquitin ligase interacting protein, NDFIP2, which interacts with multiple members of the C2-WWW-HECT domain E3 family of ligases. Liver disease is a universal feature of this disorder, characterized by a ductal plate malformation (DPM) that leads to increased number of irregularly shaped and dilated biliary ductules, with variable degrees of associated fibrosis. The protein localizes to the primary cilium and other sub-cellular locations where it may function as a receptor for an unidentified ligand[13,14,15,16,17] It undergoes a complicated Notch-like pattern of proteolytic processing whose activity may be regulated, possibly by ligand-binding[18, 19]. The functions of the full-length protein, its various isoforms and proteolytic products remain poorly defined
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