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The bradykinin B2 receptor induces multiple cellular responses leading to the proliferation of human renal carcinoma cell lines

DOI: http://dx.doi.org/10.2147/CMAR.S31847

Keywords: A498 cells, G protein-coupled receptors, signal transduction, Na+/H+ exchange, extracellular signal-regulated protein kinase

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Abstract:

radykinin B2 receptor induces multiple cellular responses leading to the proliferation of human renal carcinoma cell lines Original Research (27579) Total Article Views Authors: Kramarenko II, Morinelli TA, Bunni MA, Raymond JR Sr, Garnovskaya MN Published Date July 2012 Volume 2012:4 Pages 195 - 205 DOI: http://dx.doi.org/10.2147/CMAR.S31847 Received: 16 March 2012 Accepted: 02 May 2012 Published: 26 July 2012 Inga I Kramarenko1, Thomas A Morinelli1,2, Marlene A Bunni1,2, John R Raymond Sr3, Maria N Garnovskaya1 1Department of Medicine (Nephrology Division), Medical University of South Carolina, Charleston, SC, USA; 2Medical and Research Services of the Ralph H Johnson Veterans Affairs Medical Center, Charleston, SC, USA; 3Medical College of Wisconsin, Milwaukee, WI, USA Background: The vasoactive peptide bradykinin (BK) acts as a potent growth factor for normal kidney cells, but there have been few studies on the role of BK in renal cell carcinomas. Purpose: In this study, we tested the hypothesis that BK also acts as a mitogen in kidney carcinomas, and explored the effects of BK in human renal carcinoma A498 cells. Methods: The presence of mRNAs for BK B1 and BK B2 receptors in A498 cells was demonstrated by reverse transcription–polymerase chain reaction. To study BK signaling pathways, we employed fluorescent measurements of intracellular Ca2+, measured changes in extracellular pH as a reflection of Na+/H+ exchange (NHE) with a Cytosensor microphysiometer, and assessed extracellular signal-regulated kinase (ERK) activation by Western blotting. Results: Exposure to 100 nM of BK resulted in the rapid elevation of intracellular Ca2+, caused a ≥30% increase in NHE activity, and a ≥300% increase in ERK phosphorylation. All BK signals were blocked by HOE140, a BK B2 receptor antagonist, but not by a B1 receptor antagonist. Inhibitor studies suggest that BK-induced ERK activation requires phospholipase C and protein kinase C activities, and is Ca2+/calmodulin-dependent. The amiloride analog 5-(N-methyl-N-isobutyl)-amiloride (MIA) blocked short-term NHE activation and inhibited ERK phosphorylation, suggesting that NHE is critical for ERK activation by BK. BK induced an approximately 40% increase in the proliferation of A498 cells as assessed by bromodeoxyuridine uptake. This effect was blocked by the ERK inhibitor PD98059, and was dependent on NHE activity. Conclusion: We conclude that BK exerts mitogenic effects in A498 cells via the BK B2 receptor activation of growth-associated NHE and ERK.

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