Pdcd10-Stk24/25 complex controls kidney water reabsorption by regulating Aqp2 membrane targeting
Rui Wang, … , Yin Xia, Xiangjian Zheng
Rui Wang, … , Yin Xia, Xiangjian Zheng
Published June 22, 2021
Citation Information: JCI Insight. 2021;6(12):e142838. https://doi.org/10.1172/jci.insight.142838.
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Research Article Nephrology

Pdcd10-Stk24/25 complex controls kidney water reabsorption by regulating Aqp2 membrane targeting

Abstract

PDCD10, also known as CCM3, is a gene found to be associated with the human disease cerebral cavernous malformations (CCMs). PDCD10 forms a complex with GCKIII kinases including STK24, STK25, and MST4. Studies in C. elegans and Drosophila have shown a pivotal role of the PDCD10-GCKIII complex in maintaining epithelial integrity. Here, we found that mice deficient of Pdcd10 or Stk24/25 in the kidney tubules developed polyuria and displayed increased water consumption. Although the expression levels of aquaporin genes were not decreased, the levels of total and phosphorylated aquaporin 2 (Aqp2) protein in the apical membrane of tubular epithelial cells were decreased in Pdcd10- and Stk24/25-deficient mice. This loss of Aqp2 was associated with increased expression and membrane targeting of Ezrin and phosphorylated Ezrin, Radixin, Moesin (p-ERM) proteins and impaired intracellular vesicle trafficking. Treatment with Erlotinib, a tyrosine kinase inhibitor promoting exocytosis and inhibiting endocytosis, normalized the expression level and membrane abundance of Aqp2 protein, and partially rescued the water reabsorption defect observed in the Pdcd10-deficient mice. Our current study identified the PDCD10-STK-ERM signaling pathway as a potentially novel pathway required for water balance control by regulating vesicle trafficking and protein abundance of AQP2 in the kidneys.

Authors

Rui Wang, Shi-Ting Wu, Xi Yang, Yude Qian, Jaesung P. Choi, Rui Gao, Siliang Song, Yixuan Wang, Tao Zhuang, Justin J.L. Wong, Yuzhen Zhang, Zhiming Han, Hua A. Lu, Stephen I. Alexander, Renjing Liu, Yin Xia, Xiangjian Zheng

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Figure 6

Pdcd10 deletion increases Ezrin and p-ERM protein abundance and membrane targeting.

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Pdcd10 deletion increases Ezrin and p-ERM protein abundance and membran...
(A and B) Immunofluorescence staining of Ezrin and p-ERM demonstrates the protein level of both Ezrin and p-ERM are increased in the medulla of Pdcd10-deficient kidneys correlated to the decreased expression of Aqp2 (dashed lines indicate the boundaries between cortex and medulla). (C and D) High-power confocal images show the increased expression and luminal membrane localization of Ezrin (C) and p-ERM (D) in tubular cells of the inner medulla of Pdcd10-deficient kidneys. Overlay images with Aqp2 staining demonstrate that the increased expression of Ezrin and p-ERM is correlated with the decreased expression and diffused distribution of Aqp2 in tubular cells in Pdcd10-deficient mice. The images shown are representative of 3 experiments with kidney samples from mutant and littermate control mice at 4 or 8weeks of age. (E) The quantification of mean fluorescence intensity of Ezrin and Aqp2 (left) in medulla (Pdcd10fl/fl, n = 11; Pdcd10KspKO, n = 6), and p-ERM and Aqp2 (right) in medulla (n = 10 for each group). (F) Relative expression level of Ezrin, Radixin, and Moesin genes in the total kidney and medulla of control and Pdcd10-deficient mice at 4 weeks of age (n = 3–4 for each group). (G) Western blots of Ezrin protein in the renal medulla of control and Pdcd10KspKO mice at 8 weeks of age. Data are presented as mean ± SEM using unpaired t test. ***P < 0.001; *P < 0.05. Original magnification, ×40 (A and B); ×630 (C and D).”