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Polycystin‐1 and Gα12 regulate epithelial‐mesenchymal transition in renal epithelial cells
Author(s) -
Xu Jen,
Racioppi Ryan,
Kong Zhanglin,
Wu Yong,
Li Suyan,
Lu TzongShi,
Kong Tianqing
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.927.13
Subject(s) - autosomal dominant polycystic kidney disease , epithelial–mesenchymal transition , adam10 , cadherin , cancer research , polycystic kidney disease , kidney , vimentin , pkd1 , chemistry , microbiology and biotechnology , pathology , biology , medicine , cell , endocrinology , matrix metalloproteinase , metalloproteinase , cancer , metastasis , immunohistochemistry , disintegrin , biochemistry
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary diseases. Mutations in polycystin‐1 (PC1) and polycystin‐2 (PC2) account for the etiology of 85% and 15% of cases, respectively. Its pathology of cystogenesis and deterioration of kidney function includes focal inflammation, fibrosis, and disruption of cell polarity, cell‐cell, and cell‐matrix adhesions. Epithelial‐mesenchymal transition (EMT) is also a tubulointerstitial pathology in ADPKD. However, the specific mechanism for EMT in the kidneys of ADPKD remains poorly understood. In Madin‐Darby canine kidney (MDCK) cells, active Gα12 caused the differential shedding of E‐cadherin and N‐cadherin. Further study showed that deletion of Pkd1 led to activation of Gα12, increased the shedding of E‐cadherin in mouse kidney. In addition, we found that a disintegrin and metalloproteinase domain‐containing protein 10 (ADAM10) was the key sheddase. This differential cleavage of E‐cadherin and N‐cadherin results in the switch from E‐cadherin to N‐cadherin that was observed in kidney tissue from ADPKD mice and patients. Gα12 activation or Pkd1 deletion led to the transition of β‐catenin from cell membrane to nucleus and increased levels of EMT markers (α‐SMA, vimentin). The specific ADAM10 inhibitor GI254023X blocked the E‐cadherin to N‐cadherin switch and reduced the EMT markers. Our results demonstrate a novel mechanism of EMT in ADPKD. Inhibition of this pathway, especially of ADAM10 activity, could be a novel therapeutic regimen for ADPKD.