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

Abstract

BackgroundThe 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.PurposeIn 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.MethodsThe 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.ResultsExposure 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.ConclusionWe conclude that BK exerts mitogenic effects in A498 cells via the BK B2 receptor activation of growth-associated NHE and ERK.

Bradykinin regulates cell growth and migration in cultured human cardiac c-Kit+ progenitor cells

“…The mitogenic effect of bradykinin mediated by G protein-coupled B2Rs involving MEK/MAPK is observed in epithelial breast cancer cells [35], bovine tracheal smooth muscle cells [36], and also human renal carcinoma A498 cells [37]. Bradykinin acts as a proliferative agent in MCF-7 cells by activating intracellular pathways including PKC, pAkt and pERK1/2 [38].…”

“…Earlier studies demonstrated that bradykinin displays a wide range of biological activities in different tissues, including regulation of mitogenesis in several cell types [ 34 ]. The mitogenic effect of bradykinin mediated by G protein-coupled B2Rs involving MEK/MAPK is observed in epithelial breast cancer cells [ 35 ], bovine tracheal smooth muscle cells [ 36 ], and also human renal carcinoma A498 cells [ 37 ]. Bradykinin acts as a proliferative agent in MCF-7 cells by activating intracellular pathways including PKC, pAkt and pERK1/2 [ 38 ].…”

A modular map of Bradykinin-mediated inflammatory signaling network

“…In A549 lung epithelial cells, bradykinin requires G q/11 to activate and MAPK14, which induces the phosphorylation of EGFR at Ser 1047 and upregulates the transcription of dual-specificity MAPK phosphatase 5 (DUSP5) (Izumi et al 2018). Bradykinin mediated B2R activation leads to cell proliferation in renal carcinoma A498 cells through MAPK1/3 and NHE1 pathways (Kramarenko et al 2012). Also, bradykinin/B2R promoted the proliferation, migration, and invasion of cervical cancer cells via the STAT3 signaling pathway by upregulating the expression of MMP-2, MMP-9 and downregulating the expression pro-apoptotic protein cleaved caspase-9 (Yang et al 2009;Wang et al 2019).…”

Renin angiotensin system deregulation as renal cancer risk factor (Review)

“…Kramarenko discovered that bradykinin promotes the proliferation of RCC cells (A498 cell line) through the B2 receptor. This activation is dependent on the PLC, PKC, and ERK pathways, as well as on Ca2+/Cam activity ( 49 ). Thus, the increased concentration of bradykinin observed in ACEI users may promote carcinogenesis and tumor cell proliferation.…”