%0 Journal Article %T The bradykinin B2 receptor induces multiple cellular responses leading to the proliferation of human renal carcinoma cell lines %A Kramarenko II %A Morinelli TA %A Bunni MA %A Raymond JR Sr %A Garnovskaya MN %J Cancer Management and Research %D 2012 %I %R http://dx.doi.org/10.2147/CMAR.S31847 %X 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¨Cpolymerase 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 ¡Ý30% increase in NHE activity, and a ¡Ý300% 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. %K A498 cells %K G protein-coupled receptors %K signal transduction %K Na+/H+ exchange %K extracellular signal-regulated protein kinase %U https://www.dovepress.com/the-bradykinin-b2-receptor-induces-multiple-cellular-responses-leading-peer-reviewed-article-CMAR