Differential bradykinin B1 and B2 receptor regulation on cell death induced by hepatic ischemia-reperfusion injury

• Grant number: 14/19197-1
• Support Opportunities: Regular Research Grants - Publications - Scientific article
• Start date: November 01, 2014
• End date: April 30, 2015
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Márcia Regina Nagaoka
• Grantee: Márcia Regina Nagaoka
• Host Institution: Instituto de Saúde e Sociedade (ISS). Universidade Federal de São Paulo (UNIFESP). Campus Baixada Santista. Santos , SP, Brazil

Abstract

Biological and pharmacological effects of bradykinin (BK) are mediated by two receptors: the constitutive B2 (B2R) and the inducible B1 (B1R). BK has a role in the hepatic microcirculation by induction of portal hypertensive response (PHR) via B2R, since des-arg9-BK (DABK), a B1R agonist, did not elicit response. During ischemia-reperfusion injury, important changes in the microcirculation have been observed and cell death by necrosis and apoptosis is the main event involved in the poor function of the graft. The aim of this work is to analyze the role of B1R and B2R on liver cell death induced by ischemia-reperfusion injury. Wistar rat livers were submitted to ischemia (4oC) for 4 h or 24 h. After this period, livers were reperfused ex vivo with Krebs-Henseleit solution (37oC). Agonists BK or DABK was injected in bolus during the reperfusion, in the presence or absence of respective antagonists HOE-140 (B2R) or des-arg9-[leu8]-BK (B1R). Liver viability was analyzed by glucose release and bile secretion. PHR to kinins was analyzed. Cell death was analyzed by Cell Death ELISA (Roche), Trypan blue exclusion (necrosis) and TUNEL (apoptosis). We observed that PHR did not change. Cell death was higher in the DABK group and its antagonist decreased significantly the cell death. Interestingly, B1R antagonist did not alter the number of necrotic cells, but decreased the number of apoptotic cells. On the other hand, B2R antagonist decreased the number of necrotic cells, and did not alter the number of apoptotic cells. Therefore, B1R may participate in cell death signaling of apoptosis, whereas B2R may be involved in cell death by necrosis. (AU)