{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The bradykinin B2 receptor (BDKRB2) is a constitutively expressed G protein–coupled receptor that plays a pivotal role in mediating a wide range of physiological and pathophysiological processes. In the central nervous system, activation of BDKRB2 elicits intracellular calcium oscillations that promote glioma cell migration and invasion by acting as a chemoattractant guiding cells toward blood vessels."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the kidney, BDKRB2—in cooperation with B1 receptors—contributes to tissue protection; combined deletion of these receptors exacerbates diabetic nephropathy and ischemia/reperfusion injury by amplifying oxidative stress, fibrogenic responses, and cellular damage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, BDKRB2 signaling mediates the recruitment of circulating angiogenic progenitor cells to ischemic sites through phosphoinositide 3-kinase and eNOS‐dependent mechanisms, thereby facilitating vascular repair."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In certain cancers, such as colorectal carcinoma, BDKRB2 activation upregulates ERK1/2 and interleukin‑6 production to enhance cell invasion and migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Localization studies further reveal that BDKRB2 is enriched in caveolae‐associated lipid rafts—an arrangement that appears to promote precise receptor recycling and efficient signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In addition, genetic polymorphisms in BDKRB2 can influence vascular tone and modulate the antihypertensive efficacy of ACE inhibitors"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", while its acute activation also plays a central role in inducing vascular leakage during inflammatory conditions such as angioedema."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Finally, BDKRB2 signaling is implicated in the regulation of epithelial sodium channels under high-sodium conditions, thereby contributing to natriuresis independent of aldosterone."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Vedrana Montana, Harald Sontheimer "}, {"type": "b", "children": [{"type": "t", "text": "Bradykinin promotes the chemotactic invasion of primary brain tumors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.3825-10.2011"}], "href": "https://doi.org/10.1523/JNEUROSCI.3825-10.2011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21451024"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21451024"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Masao Kakoki, Kelli A Sullivan, Carey Backus, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1005144107"}], "href": "https://doi.org/10.1073/pnas.1005144107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20479236"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20479236"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Masao Kakoki, Robert W McGarrah, Hyung-Suk Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0701617104"}], "href": "https://doi.org/10.1073/pnas.0701617104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17452647"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17452647"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Nicolle Kränkel, Rajesh G Katare, Mauro Siragusa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of kinin B2 receptor signaling in the recruitment of circulating progenitor cells with neovascularization potential."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.108.179952"}], "href": "https://doi.org/10.1161/CIRCRESAHA.108.179952"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18927465"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18927465"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Guojun Wang, Yanwei Ye, Xiefu Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bradykinin stimulates IL-6 production and cell invasion in colorectal cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.2014.3366"}], "href": "https://doi.org/10.3892/or.2014.3366"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25109623"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25109623"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Maria E Lamb, Chongwu Zhang, Thomas Shea, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human B1 and B2 bradykinin receptors and their agonists target caveolae-related lipid rafts to different degrees in HEK293 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi020231d"}], "href": "https://doi.org/10.1021/bi020231d"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12450400"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12450400"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "P S Silva, V Fontana, M R Luizon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "eNOS and BDKRB2 genotypes affect the antihypertensive responses to enalapril."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Clin Pharmacol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00228-012-1326-2"}], "href": "https://doi.org/10.1007/s00228-012-1326-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22706620"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22706620"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Fleur Bossi, Fabio Fischetti, Domenico Regoli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel pathogenic mechanism and therapeutic approaches to angioedema associated with C1 inhibitor deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Allergy Clin Immunol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jaci.2009.08.007"}], "href": "https://doi.org/10.1016/j.jaci.2009.08.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19796797"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19796797"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Mykola Mamenko, Oleg Zaika, Peter A Doris, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Salt-dependent inhibition of epithelial Na+ channel-mediated sodium reabsorption in the aldosterone-sensitive distal nephron by bradykinin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hypertension (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/HYPERTENSIONAHA.112.200469"}], "href": "https://doi.org/10.1161/HYPERTENSIONAHA.112.200469"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23033373"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23033373"}]}]}]}