Polycystin-1 maturation requires polycystin-2 in a dose-dependent manner
Vladimir G. Gainullin, … , Cynthia J. Hommerding, Peter C. Harris
Vladimir G. Gainullin, … , Cynthia J. Hommerding, Peter C. Harris
Published January 9, 2015
Citation Information: J Clin Invest. 2015;125(2):607-620. https://doi.org/10.1172/JCI76972.
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Research Article

Polycystin-1 maturation requires polycystin-2 in a dose-dependent manner

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited nephropathy responsible for 4%–10% of end-stage renal disease cases. Mutations in the genes encoding polycystin-1 (PC1, PKD1) or polycystin-2 (PC2, PKD2) cause ADPKD, and PKD1 mutations are associated with more severe renal disease. PC1 has been shown to form a complex with PC2, and the severity of PKD1-mediated disease is associated with the level of the mature PC1 glycoform. Here, we demonstrated that PC1 and PC2 first interact in the ER before PC1 cleavage at the GPS/GAIN site and determined that PC2 acts as an essential chaperone for PC1 maturation and surface localization. The chaperone function of PC2 was dependent on the presence of the distal coiled-coil domain and was disrupted by pathogenic missense mutations. In Pkd2–/– mice, complete loss of PC2 prevented PC1 maturation. In Pkd2 heterozygotes, the 50% PC2 reduction resulted in a nonequimolar reduction (20%–25%) of the mature PC1 glycoform. Interbreeding between various Pkd1 and Pkd2 models revealed that animals with reduced levels of functional PC1 and PC2 in the kidney exhibited severe, rapidly progressive disease, illustrating the importance of complexing of these proteins for function. Our results indicate that PC2 regulates PC1 maturation; therefore, mature PC1 levels are a determinant of disease severity in PKD2 as well as PKD1.

Authors

Vladimir G. Gainullin, Katharina Hopp, Christopher J. Ward, Cynthia J. Hommerding, Peter C. Harris

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Figure 6

Pkd2 depletion aggravates the Pkd1RC/RC cystic phenotype.

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Pkd2 depletion aggravates the Pkd1RC/RC cystic phenotype. (A) Masson tr...
(A) Masson trichrome–stained kidney cross sections of 4-month-old mice of the Pkd1RC/RC genotype with the addition of Pkd2WS25/+, Pkd2+/–, or Pkd2WS25/–, and Pkd2WS25/– mice with the Pkd1RC/+ genotype. PKD severity and fibrosis worsened in bigenic mice, with evidently more severe disease in the Pkd1RC/RC Pkd2+/– genotype, corresponding to PC1-NTR levels of about 30% (Figure 5C). However, the Pkd1RC/RC Pkd2WS25/– combination resulted in the most severe disease. Scale bar: 1 mm. (B–D) Graphical representations of %KW/BW (B), cystic index (C), and blood urea nitrogen (D) of the various genotypes quantify the increased disease severity with Pkd1/Pkd2 combined phenotypes (see Supplemental Table 1 for details). Error bars depict ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 using a 2-way ANOVA with Student’s t test. F, female; M, male. +Note that 5 of 10 Pkd1RC/RC Pkd2WS25/– animals died before 4 months (F: P42, P74; M: P38, P51, P79).