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Expression and secretion of CXCL12 are enhanced in autosomal dominant polycystic kidney disease
Hyunho Kim1, Jinmo Sung1, Hyunsuk Kim2, Hyunjin Ryu3, Hayne Cho Park4, Yun Kyu Oh5, Hyun-seob Lee6, Kook-Hwan Oh3, Curie Ahn3,*, Curie Ahn3,*
1Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital,
2Internal Medicine, Hallym University Medical Center, Chuncheon Sacred Heart Hospital,
3Department of Internal Medicine, Seoul National University College of Medicine,
4Department of Internal Medicine, Hallym University Medical Center, Kangnam Sacred Heart Hospital,
5Department of Internal Medicine, Seoul National University, Boramae Medical Center,
6Genomics Core Facility, Department of Transdisciplinary Research and Collaboration, Biomedical Resea, Seoul National University Hospital
Abstract
Autosomal dominant polycystic kidney disease (ADPKD), one of the most common human monogenic diseases (frequency of 1/1000~1/400), is characterized by numerous fluid-filled renal cysts (RCs). Inactivation of the PKD1 or PKD2 gene by germline and somatic mutations is necessary for cyst formation in ADPKD. To mechanistically understand cyst formation and growth, we isolated RCs from Korean patients with ADPKD and immortalized them with human telomerase reverse transcriptase (hTERT). Three hTERT-immortalized RC cell lines were characterized as proximal epithelial cells with germline and somatic PKD1 mutations. Thus, we first established hTERT-immortalized proximal cyst cells with somatic PKD1 mutations.
Through transcriptome sequencing and Gene Ontology (GO) analysis, we found that upregulated genes were related to cell division and that downregulated genes were related to cell differentiation. We wondered whether the upregulated gene for the chemokine CXCL12 is related to the mTOR signaling pathway in cyst growth in ADPKD. CXCL12 mRNA expression and secretion were increased in RC cell lines. We then examined CXCL12 levels in RC fluids from patients with ADPKD and found increased CXCL12 levels. The CXCL12 receptor CXC chemokine receptor 4 (CXCR4) was upregulated, and the mTOR signaling pathway, which is downstream of the CXCL12/CXCR4 axis, was activated in ADPKD kidney tissue. To confirm activation of the mTOR signaling pathway by CXCL12 via CXCR4, we treated the RC cell lines with recombinant CXCL12 and the CXCR4 antagonist AMD3100; CXCL12 induced the mTOR signaling pathway, but the CXCR4 antagonist AMD3100 blocked the mTOR signaling pathway. Taken together, these results suggest that enhanced CXCL12 in RC fluids activates the mTOR signaling pathway via CXCR4 in ADPKD cyst growth.
Abstract, Accepted Manuscript(in press) [Submitted on April 17, 2019, Accepted on May 23, 2019]
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