The up-regulated kinin B1 receptors exert a pivotal role in modulating inflammatory processes. In isolated human umbilical vein (HUV), kinin B1 receptor is up-regulated as a function of in vitro incubation time and pro-inflammatory stimuli. The aim of this study was to evaluate the involvement of extracellular signal-regulated kinase 5 (ERK5), p38 MAPK, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2) on kinin B1 receptor up-regulation process in HUV, employing functional and biochemical methods. Real time PCR analysis revealed for the first time that kinin B1 receptor mRNA expression closely parallels the functional sensitization to kinin B1 receptor selective agonist des-Arg10-Kallidine (DAKD) in HUV. Moreover, the selective inhibition of ERK5, p38 MAPK and JNK, but not ERK1/2 produced a dose-dependent rightward shift of the concentration-response curves (CRC) to DAKD after 5h-incubation and a reduction in kinin B1 receptor mRNA expression. Biochemical analyses showed that ERK5, p38 MAPK and JNK phosphorylation is maximal during the first 2-h post-isolation followed by a significant reduction in the last 3-h. None of the treatments modified the responses to serotonin (5-HT), an unrelated agonist, suggesting a specific effect on kinin B1 receptor up-regulation. The present work provides for the first time pharmacological evidence indicating that ERK5 plays a significant role on kinin B1 receptor up-regulation. Furthermore, we confirm the relevance of p38 MAPK and JNK as well as the lack of effect of ERK1/2 in this process. This study may contribute for a better understanding of MAPK involvement in inflammatory and immunological diseases.
- The American Society for Pharmacology and Experimental Therapeutics