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This Article Full Text Full Text (PDF) All Versions of this Article: ASN.2005060645v1 17/1/178    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamaguchi, T. Articles by Wallace, D. P. Search for Related Content PubMed PubMed Citation Articles by Yamaguchi, T. Articles by Wallace, D. P. Related Collections Related Article

Calcium Restores a Normal Proliferation Phenotype in Human Polycystic Kidney Disease Epithelial Cells

Tamio Yamaguchi^*,, Scott J. Hempson^*,, Gail A. Reif^*,, Anne-Marie Hedge^*, and Darren P. Wallace^*,,

^* Kidney Institute, Departments of Medicine and Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas

Address correspondence to: Dr. Darren P. Wallace, Kidney Institute, Department of Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, MSN 3018, Kansas City, KS 66160. Phone: 913-588-3889; Fax: 913-588-9251; E-mail: dwallace{at}kumc.edu

Received for publication June 21, 2005. Accepted for publication October 3, 2005.

Polycystic kidney disease (PKD) is a lethal disorder characterized by progressive expansion of renal cysts. Genetic mutations associated with PKD are thought to disrupt intracellular Ca²⁺ regulation, leading to abnormal proliferation of tubule epithelial cells. cAMP stimulates the B-Raf/MEK/extracellular signal-regulated kinase (B-Raf/MEK/ERK) pathway and accelerates the proliferation of cells that are cultured from PKD cysts. By contrast, cAMP inhibits the proliferation of cells from normal human kidneys (NHK) and M-1 mouse collecting duct cells. Previously, it was found that a sustained reduction of intracellular Ca²⁺ levels in NHK and M-1 cells that were treated with Ca²⁺ entry blockers allowed cAMP activation of the B-Raf/MEK/ERK pathway, switching the cells to a cAMP-growth stimulated phenotype. In this study, primary cultures of cyst epithelial cells from autosomal dominant (ADPKD) and recessive (ARPKD) PKD kidneys were used to determine whether controlled addition of Ca²⁺ could reverse the aberrant mitogenic response to cAMP. Steady-state intracellular Ca²⁺ levels were found to be 20 nM lower in cyst-derived ADPKD cells (57 ± 2 nM) compared with NHK cells (77 ± 2 nM). Treatment of ADPKD cells or ARPKD cells with either Bay K8644, a Ca²⁺ channel activator, or A23187, a Ca²⁺ ionophore, caused sustained increases in intracellular Ca²⁺ levels and completely reversed the mitogenic response to cAMP. Elevation of intracellular Ca²⁺ levels in ADPKD cells increased Akt activity and blocked cAMP-dependent B-Raf and ERK activation. Thus, increases in [Ca²⁺]_i are able to restore the normal anti-mitogenic response to cAMP in cells that are derived from two genetically distinct forms of PKD.

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