Abstract
Transgenic and gene-targeting technologies allowing the generation of genetically altered animal models have greatly advanced our understanding of the function of specific genes. This is also true for the kallikrein-kinin system (KKS), in which some, but not yet all, components have been functionally characterized using such techniques. The first genetically altered animal model for a KKS component was supplied by nature, the brown Norway rat carrying an inactivating mutation in the kininogen gene. Mice deficient in tissue kallikrein, B1 and B2 receptors, some kinin-degrading enzymes, and factor XII followed, together with transgenic rat and mouse strains overexpressing tissue kallikrein, B1 and B2 receptors, and degrading enzymes. There are still no animal models with genetic alterations in plasma kallikrein, kininases I and some other degrading enzymes. The models have confirmed an important role of the KKS in cardiovascular pathology, inflammation, and pain, and have partially elucidated the distinct function of the two receptors. This created the basis for rational decisions concerning the putative use of kinin receptor agonists and antagonists in therapeutic applications. However, a more thorough analysis of the existing models and the generation of new, more sophisticated transgenic models will be necessary to clarify the still elusive issue as to where and by which mechanisms the kinins exert their actions.
References
Alenina, N., Baltatu, O., and Bader, M. (2006). Brain renin-angiotensin system – focus on transgenic animal models. In: Molecular Mechanisms in Hypertension (London, UK: Taylor and Francis Medical Books), in press.Search in Google Scholar
Alfie, M.E., Yang, X.P., Hess, F., and Carretero, O.A. (1996). Salt-sensitive hypertension in bradykinin B2 receptor knockout mice. Biochem. Biophys. Res. Commun.224, 625–630.10.1006/bbrc.1996.1076Search in Google Scholar
Araujo, R.C., Kettritz, R., Fichtner, I., Paiva, A.C., Pesquero, J.B., and Bader, M. (2001). Altered neutrophil homeostasis in kinin B1 receptor-deficient mice. Biol. Chem.382, 91–95.10.1515/BC.2001.014Search in Google Scholar
Araujo, R.C., Mori, M.A., Merino, V.F., Bascands, J.-L., Schanstra, J.P., Pesquero, J.L., Zollner, R.L., Villela, C.A., Paiva, A.C.M., Bader, M., and Pesquero, J.B. (2005). Hypoinsulinemia and pancreatic islet dysfunction in kinin B1 receptor deficient mice. In: The XVIth Scientific Meeting of the Inter-American Society of Hypertension, Cancun, Mexico, April 17–21, 2005.Search in Google Scholar
Azizi, M., Boutouyrie, P., Bissery, A., Agharazii, M., Verbeke, F., Stern, N., Bura-Riviere, A., Laurent, S., Alhenc-Gelas, F., and Jeunemaitre, X. (2005). Arterial and renal consequences of partial genetic deficiency in tissue kallikrein activity in humans. J. Clin. Invest.115, 780–787.10.1172/JCI200523669Search in Google Scholar
Barbara, G., De Giorgio, R., Stanghellini, V., Corinaldesi, R., Cremon, C., Gerard, N., Gerard, C., Grady, E.F., Bunnett, N.W., Blennerhassett, P.A., and Collins, S.M. (2003). Neutral endopeptidase (EC 3.4.24.11) downregulates the onset of intestinal inflammation in the nematode infected mouse. Gut52, 1457–1464.Search in Google Scholar
Bergaya, S., Meneton, P., Bloch-Faure, M., Mathieu, E., Alhenc-Gelas, F., Levy, B.I., and Boulanger, C.M. (2001). Decreased flow-dependent dilation in carotid arteries of tissue kallikrein-knockout mice. Circ. Res.88, 593–599.10.1161/01.RES.88.6.593Search in Google Scholar
Bergaya, S., Matrougui, K., Meneton, P., Henrion, D., and Boulanger, C.M. (2004). Role of tissue kallikrein in response to flow in mouse resistance arteries. J. Hypertens.22, 745–750.10.1097/00004872-200404000-00017Search in Google Scholar
Bhoola, K.D., Figueroa, C.D., and Worthy, K. (1992). Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol. Rev.44, 1–80.Search in Google Scholar
Borkowski, J.A., Ransom, R.W., Seabrook, G.R., Trumbauer, M., Chen, H., Hill, R.G., Strader, C.D., and Hess, J.F. (1995). Targeted disruption of a B2 bradykinin receptor gene in mice eliminates bradykinin action in smooth muscle and neurons. J. Biol. Chem.270, 13706–13710.10.1074/jbc.270.23.13706Search in Google Scholar
Boyce, S., Rupniak, N.M., Carlson, E.J., Webb, J., Borkowski, J.A., Hess, J.F., Strader, C.D., and Hill, R.G. (1996). Nociception and inflammatory hyperalgesia in B2 bradykinin receptor knockout mice. Immunopharmacology33, 333–335.10.1016/0162-3109(96)00101-4Search in Google Scholar
Brull, D., Dhamrait, S., Myerson, S., Erdmann, J., Woods, D., World, M., Pennell, D., Humphries, S., Regitz-Zagrosek, V., and Montgomery, H. (2001). Bradykinin B2BKR receptor polymorphism and left-ventricular growth response. Lancet358, 1155–1156.10.1016/S0140-6736(01)06273-0Search in Google Scholar
Cardoso, C.C., Garrett, T., Cayla, C., Meneton, P., Pesquero, J.B., and Bader, M. (2004). Structure and expression of two kininogen genes in mice. Biol. Chem.385, 295–301.10.1515/BC.2004.025Search in Google Scholar PubMed
Carpenter, C., Honkanen, A.A., Mashimo, H., Goss, K.A., Huang, P., Fishman, M.C., Asaad, M., Dorso, C.R., and Cheung, H. (1996). Renal abnormalities in mutant mice. Nature380, 292.10.1038/380292a0Search in Google Scholar PubMed
Cervenka, L., Harrison-Bernard, L.M., Dipp, S., Primrose, G., Imig, J.D., and El-Dahr, S.S. (1999). Early onset salt-sensitive hypertension in bradykinin B2 receptor null mice. Hypertension34, 176–180.10.1161/01.HYP.34.2.176Search in Google Scholar
Cervenka, L., Vaneckova, I., Maly, J., Horacek, V., and El Dahr, S.S. (2003). Genetic inactivation of the B2 receptor in mice worsens two-kidney, one-clip hypertension: role of NO and the AT2 receptor. J. Hypertens.21, 1531–1538.10.1097/00004872-200308000-00018Search in Google Scholar
Chao, J. and Chao, L. (1996). Functional analysis of human tissue kallikrein in transgenic mouse models. Hypertension27, 491–494.10.1161/01.HYP.27.3.491Search in Google Scholar
Ciechanowicz, A., Bader, M., Wagner, J., and Ganten, D. (1993). Extra-hepatic transcription of plasma prekallikrein gene in human and rat tissues. Biochem. Biophys. Res. Commun.197, 1370–1376.10.1006/bbrc.1993.2628Search in Google Scholar
Colman, R.W., Pixley, R.A., Najamunnisa, S., Yan, W., Wang, J., Mazar, A., and McCrae, K.R. (1997). Binding of high molecular weight kininogen to human endothelial cells is mediated via a site within domains 2 and 3 of the urokinase receptor. J. Clin. Invest.100, 1481–1487.10.1172/JCI119669Search in Google Scholar
Colman, R.W., White, J.V., Scovell, S., Stadnicki, A., and Sartor, R.B. (1999). Kininogens are antithrombotic proteins in vivo. Arterioscler. Thromb. Vasc. Biol.19, 2245–2250.10.1161/01.ATV.19.9.2245Search in Google Scholar
Crackower, M.A., Sarao, R., Oudit, G.Y., Yagil, C., Kozieradzki, I., Scanga, S.E., Oliveira-dos-Santos, A.J., da Costa, J., Zhang, L., Pei, Y., et al. (2002). Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature417, 822–828.10.1038/nature00786Search in Google Scholar
Damas, J. (1996). The brown Norway rat and the kinin system. Peptides17, 859–872.10.1016/0196-9781(96)00056-3Search in Google Scholar
Day, A.L., Wick, E., Jordan, T.H., Jaffray, C.E., Bunnett, N.W., Grady, E.F., and Kirkwood, K.S. (2005). Neutral endopeptidase determines the severity of pancreatitis-associated lung injury. J. Surg. Res.128, 21–27.10.1016/j.jss.2005.03.010Search in Google Scholar
Donoghue, M., Wakimoto, H., Maguire, C.T., Acton, S., Hales, P., Stagliano, N., Fairchild-Huntress, V., Xu, J., Lorenz, J.N., Kadambi, V., et al. (2003). Heart block, ventricular tachycardia, and sudden death in ACE2 transgenic mice with downregulated connexins. J. Mol. Cell Cardiol.35, 1043–1053.10.1016/S0022-2828(03)00177-9Search in Google Scholar
Duka, I., Shenouda, S., Johns, C., Kintsurashvili, E., Gavras, I., and Gavras, H. (2001). Role of the B2 receptor of bradykinin in insulin sensitivity. Hypertension38, 1355–1360.10.1161/hy1201.096574Search in Google Scholar
El Dahr, S.S., Harrison-Bernard, L.M., Dipp, S., Yosipiv, I.V., and Meleg-Smith, S. (2000). Bradykinin B2 null mice are prone to renal dysplasia: gene-environment interactions in kidney development. Physiol. Genomics3, 121–131.10.1152/physiolgenomics.2000.3.3.121Search in Google Scholar
Emanueli, C. and Madeddu, P. (2001). Targeting kinin receptors for the treatment of tissue ischaemia. Trends Pharmacol. Sci.22, 478–484.10.1016/S0165-6147(00)01761-2Search in Google Scholar
Emanueli, C., Fink, E., Milia, A.F., Salis, M.B., Conti, M., Demontis, M.P., and Madeddu, P. (1998). Enhanced blood pressure sensitivity to deoxycorticosterone in mice with disruption of bradykinin B2 receptor gene. Hypertension31, 1278–1283.10.1161/01.HYP.31.6.1278Search in Google Scholar
Emanueli, C., Salis, M.B., Stacca, T., Pintus, G., Kirchmayr, R., Isner, J.M., Pinna, A., Gaspa, L., Regoli, D., Cayla, C., Pesquero, J.B., Bader, M., and Madeddu, P. (2002). Targeting kinin B1 receptor for therapeutic angiogenesis. Circulation105, 360–366.10.1161/hc0302.102142Search in Google Scholar
Esther, C.R. Jr., Howard, T.E., Marino, E.M., Goddard, J.M., Capecchi, M.R., and Bernstein, K.E. (1996). Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility. Lab. Invest.74, 953–965.Search in Google Scholar
Ferreira, J., Campos, M.M., Pesquero, J.B., Araujo, R.C., Bader, M., and Calixto, J.B. (2001). Evidence for the participation of kinins in Freund's adjuvant-induced inflammatory and nociceptive responses in kinin B1 and B2 receptor knockout mice. Neuropharmacology41, 1006–1012.10.1016/S0028-3908(01)00142-3Search in Google Scholar
Ferreira, J., Campos, M.M., Araujo, R.C., Bader, M., Pesquero, J.B., and Calixto, J.B. (2002). The use of kinin B1 and B2 receptor knockout mice and selective antagonists to characterize the nociceptive responses caused by kinins at the spinal level. Neuropharmacology43, 1188–1197.10.1016/S0028-3908(02)00311-8Search in Google Scholar
Ferreira, J., Beirith, A., Mori, M.A.S., Araujo, R.C., Bader, M., Pesquero, J.B., and Calixto, J.B. (2005). Reduced nerve injury-induced neuropathic pain in kinin B1 receptor knockout mice. J. Neurosci.25, 2405–2412.10.1523/JNEUROSCI.2466-04.2005Search in Google Scholar
Fischer, H.S., Zernig, G., Hauser, K.F., Gerard, C., Hersh, L.B., and Saria, A. (2002). Neutral endopeptidase knockout induces hyperalgesia in a model of visceral pain, an effect related to bradykinin and nitric oxide. J. Mol. Neurosci.18, 129–134.10.1385/JMN:18:1-2:129Search in Google Scholar
Fox, A., Kaur, S., Li, B., Panesar, M., Saha, U., Davis, C., Dragoni, I., Colley, S., Ritchie, T., Bevan, S., et al. (2005). Antihyperalgesic activity of a novel nonpeptide bradykinin B1 receptor antagonist in transgenic mice expressing the human B1 receptor. Br. J. Pharmacol.144, 889–899.10.1038/sj.bjp.0706139Search in Google Scholar
Fu, Y., Katsuya, T., Matsuo, A., Yamamoto, K., Akasaka, H., Takami, Y., Iwashima, Y., Sugimoto, K., Ishikawa, K., Ohishi, M., Rakugi, H., and Ogihara, T. (2004). Relationship of bradykinin B2 receptor gene polymorphism with essential hypertension and left ventricular hypertrophy. Hypertens. Res.27, 933–938.10.1291/hypres.27.933Search in Google Scholar
Gabra, B., Merino, V.F., Bader, M., and Sirois, P. (2005). Impairment of diabetic hyperalgesia in bradykinin B1 receptor-deficient mice. Regul. Pept.127, 245–248.10.1016/j.regpep.2004.12.003Search in Google Scholar
Griol-Charhbili, V., Messadi-Laribi, E., Bascands, J.L., Heudes, D., Meneton, P., Giudicelli, J.F., Alhenc-Gelas, F., and Richer, C. (2005). Role of tissue kallikrein in the cardioprotective effects of ischemic and pharmacological preconditioning in myocardial ischemia. FASEB J.19, 1172–1174.10.1096/fj.04-3508fjeSearch in Google Scholar
Harrison-Bernard, L.M., Dipp, S., and El Dahr, S.S. (2003). Renal and blood pressure phenotype in 18-mo-old bradykinin B2R-/- CRD mice. Am. J. Physiol. Regul. Integr. Comp. Physiol.285, R782–R790.10.1152/ajpregu.00133.2003Search in Google Scholar
Hayashi, I., Ohishi, S., Kato, H., Enjyoji, K., Iwanaga, S., and Nakano, T. (1985). Identification of T-kininogen in high and low molecular weight kininogens deficient rat (brown Norway Katholiek strain). Thromb. Res.39, 313–321.10.1016/0049-3848(85)90227-0Search in Google Scholar
Hayashi, I., Hoshiko, S., Makabe, O., and Ohishi, S. (1993). A point mutation of alanine 163 to threonine is responsible for the defective secretion of high molecular weight kininogen by the liver of brown Norway Katholiek rats. J. Biol. Chem.268, 17219–17224.10.1016/S0021-9258(19)85325-5Search in Google Scholar
Hellal, F., Pruneau, D., Palmier, B., Faye, P., Croci, N., Plotkine, M., and Marchand-Verrecchia, C. (2003). Detrimental role of bradykinin B2 receptor in a murine model of diffuse brain injury. J. Neurotrauma20, 841–851.10.1089/089771503322385773Search in Google Scholar PubMed
Hess, J.F., Ransom, R.W., Zeng, Z., Chang, R.S., Hey, P.J., Warren, L., Harrell, C.M., Murphy, K.L., Chen, T.B., Miller, P.J., et al. (2004). Generation and characterization of a human bradykinin receptor B1 transgenic rat as a pharmacodynamic model. J. Pharmacol. Exp. Ther.310, 488–497.10.1124/jpet.104.066886Search in Google Scholar PubMed
Hilgers, R.H., Bergaya, S., Schiffers, P.M., Meneton, P., Boulanger, C.M., Henrion, D., Levy, B.I., and De Mey, J.G. (2003). Uterine artery structural and functional changes during pregnancy in tissue kallikrein-deficient mice. Arterioscler. Thromb. Vasc. Biol.23, 1826–1832.10.1161/01.ATV.0000090672.07568.60Search in Google Scholar PubMed
Ikeda, Y., Hayashi, I., Kamoshita, E., Yamazaki, A., Endo, H., Ishihara, K., Yamashina, S., Tsutsumi, Y., Matsubara, H., and Majima, M. (2004). Host stromal bradykinin B2 receptor signaling facilitates tumor-associated angiogenesis and tumor growth. Cancer Res.64, 5178–5185.10.1158/0008-5472.CAN-03-3589Search in Google Scholar PubMed
Imig, J.D., Zhao, X., Orengo, S.R., Dipp, S., and El Dahr, S.S. (2003). The bradykinin B2 receptor is required for full expression of renal COX-2 and renin. Peptides24, 1141–1147.10.1016/j.peptides.2003.07.003Search in Google Scholar PubMed
Isordia-Salas, I., Pixley, R.A., Li, F., Sainz, I., Sartor, R.B., Adam, A., and Colman, R.W. (2002). Kininogen deficiency modulates chronic intestinal inflammation in genetically susceptible rats. Am. J. Physiol. Gastrointest. Liver Physiol.283, G180–G186.10.1152/ajpgi.00514.2001Search in Google Scholar PubMed
Kakoki, M., Takahashi, N., Jennette, J.C., and Smithies, O. (2004). Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor. Proc. Natl. Acad. Sci. USA101, 13302–13305.10.1073/pnas.0405449101Search in Google Scholar PubMed PubMed Central
Kaplan, A.P., Joseph, K., and Silverberg, M. (2002). Pathways for bradykinin formation and inflammatory disease. J. Allergy Clin. Immunol.109, 195–209.10.1067/mai.2002.121316Search in Google Scholar PubMed
Kaschina, E., Stoll, M., Sommerfeld, M., Steckelings, U.M., Kreutz, R., and Unger, T. (2004). Genetic kininogen deficiency contributes to aortic aneurysm formation but not to atherosclerosis. Physiol. Genomics19, 41–49.10.1152/physiolgenomics.00035.2004Search in Google Scholar PubMed
Katada, J. and Majima, M. (2002). AT(2) receptor-dependent vasodilation is mediated by activation of vascular kinin generation under flow conditions. Br. J. Pharmacol.136, 484–491.10.1038/sj.bjp.0704731Search in Google Scholar PubMed PubMed Central
Kitamura, N., Ohkubo, H., and Nakanishi, S. (1987). Molecular biology of the angiotensinogen and kininogen genes. J. Cardiovasc. Pharmacol.10 (Suppl. 7), 49–53.10.1097/00005344-198706107-00008Search in Google Scholar PubMed
Krege, J.H., John, S.W., Langenbach, L.L., Hodgin, J.B., Hagaman, J.R., Bachman, E.S., Jennette, J.C., O'Brien, D.A., and Smithies, O. (1995). Male-female differences in fertility and blood pressure in ACE- deficient mice. Nature375, 146–148.10.1038/375146a0Search in Google Scholar PubMed
Leeb-Lundberg, L.M., Marceau, F., Müller-Esterl, W., Pettibone, D.J., and Zuraw, B.L. (2005). International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol. Rev.57, 27–77.Search in Google Scholar
Liu, Y.H., Yang, X.P., Mehta, D., Bulagannawar, M., Scicli, G.M., and Carretero, O.A. (2000). Role of kinins in chronic heart failure and in the therapeutic effect of ACE inhibitors in kininogen-deficient rats. Am. J. Physiol. Heart Circ. Physiol.278, H507–H514.10.1152/ajpheart.2000.278.2.H507Search in Google Scholar PubMed
Lu, B., Gerard, N.P., Kolakowski, L.F. Jr., Bozza, M., Zurakowski, D., Finco, O., Carroll, M.C., and Gerard, C. (1995). Neutral endopeptidase modulation of septic shock. J. Exp. Med.181, 2271–2275.10.1084/jem.181.6.2271Search in Google Scholar PubMed PubMed Central
Lu, B., Figini, M., Emanueli, C., Geppetti, P., Grady, E.F., Gerard, N.P., Ansell, J., Payan, D.G., Gerard, C., and Bunnett, N. (1997). The control of microvascular permeability and blood pressure by neutral endopeptidase. Nat. Med.3, 904–907.10.1038/nm0897-904Search in Google Scholar PubMed
Madeddu, P., Varoni, M.V., Palomba, D., Emanueli, C., Demontis, M.P., Glorioso, N., Dessi Fulgheri, P., Sarzani, R., and Anania, V. (1997). Cardiovascular phenotype of a mouse strain with disruption of bradykinin B2-receptor gene. Circulation96, 3570–3578.10.1161/01.CIR.96.10.3570Search in Google Scholar
Maestri, R., Milia, A.F., Salis, M.B., Graiani, G., Lagrasta, C., Monica, M., Corradi, D., Emanueli, C., and Madeddu, P. (2003). Cardiac hypertrophy and microvascular deficit in kinin B2 receptor knockout mice. Hypertension41, 1151–1155.10.1161/01.HYP.0000064180.55222.DFSearch in Google Scholar PubMed
Majima, M., Yoshida, O., Muto, T., Mizogami, S., Kuribayashi, Y., Katori, M., and Ohishi, S. (1993). High sensitivity to salt in kininogen-deficient brown Norway Katholiek rats. Hypertension22, 705–714.10.1161/01.HYP.22.5.705Search in Google Scholar PubMed
Majima, M., Mizogami, S., Kuribayashi, Y., Katori, M., and Ohishi, S. (1994). Hypertension induced by a nonpressor dose of angiotensin II in kininogen-deficient rats. Hypertension24, 111–119.10.1161/01.HYP.24.1.111Search in Google Scholar PubMed
Maltais, I., Bachvarova, M., Maheux, P., Perron, P., Marceau, F., and Bachvarov, D. (2002). Bradykinin B2 receptor gene polymorphism is associated with altered urinary albumin/creatinine values in diabetic patients. Can. J. Physiol. Pharmacol.80, 323–327.10.1139/y02-036Search in Google Scholar PubMed
Meneton, P., Bloch-Faure, M., Hagege, A.A., Ruetten, H., Huang, W., Bergaya, S., Ceiler, D., Gehring, D., Martins, I., Salmon, G., et al. (2001). Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice. Proc. Natl. Acad. Sci. USA98, 2634–2639.10.1073/pnas.051619598Search in Google Scholar PubMed PubMed Central
Milia, A.F., Gross, V., Plehm, R., Silva, J.A. Jr., Bader, M., and Luft, F.C. (2001). Normal blood pressure and renal function in mice lacking the bradykinin B2 receptor. Hypertension37, 1473–1479.10.1161/01.HYP.37.6.1473Search in Google Scholar PubMed
Mori, M.A., Araujo, R.C., Merino, V.F., Reis, F.G., Navarro, A., Bascands, J.L., Schanstra, J.P., Even, P.C., Pesquero, J.L., Paiva, A.C.M., et al. (2005) Protection against high fat diet-induced obesity and diabetes in kinin B1 receptor deficient mice. In: Fourth International Symposium on Obesity and Hypertension, Berlin, Germany, October 27–29, 2005.Search in Google Scholar
Ni, A., Yin, H., Agata, J., Yang, Z., Chao, L., and Chao, J. (2003). Overexpression of kinin B1 receptors induces hypertensive response to des-Arg9-bradykinin and susceptibility to inflammation. J. Biol. Chem.278, 219–225.10.1074/jbc.M209490200Search in Google Scholar PubMed
Pauer, H.U., Renne, T., Hemmerlein, B., Legler, T., Fritzlar, S., Adham, I., Muller-Esterl, W., Emons, G., Sancken, U., Engel, W., and Burfeind, P. (2004). Targeted deletion of murine coagulation factor XII gene-a model for contact phase activation in vivo. Thromb. Haemost.92, 503–508.10.1160/TH04-04-0250Search in Google Scholar PubMed
Pesquero, J.B. and Bader, M. (1998). Molecular biology of the kallikrein-kinin system: from structure to function. Braz. J. Med. Biol. Res.31, 1197–1203.10.1590/S0100-879X1998000900013Search in Google Scholar
Pesquero, J.B., Pesquero, J.L., Oliveira, S.M., Roscher, A.A., Metzger, R., Ganten, D., and Bader, M. (1996). Molecular cloning and functional characterization of a mouse bradykinin B1 receptor gene. Biochem. Biophys. Res. Commun.220, 219–225.10.1006/bbrc.1996.0384Search in Google Scholar
Pesquero, J.B., Araujo, R.C., Heppenstall, P.A., Stucky, C.L., Silva, J.A. Jr., Walther, T., Oliveira, S.M., Pesquero, J.L., Paiva, A.C., Calixto, J.B., Lewin, G.R., and Bader, M. (2000). Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors. Proc. Natl. Acad. Sci. USA97, 8140–8145.10.1073/pnas.120035997Search in Google Scholar
Pinto, Y.M., Bader, M., Pesquero, J.B., Tschöpe, C., Scholtens, E., van Gilst, W.H., and Buikema, H. (2000). Increased kallikrein expression protects against cardiac ischemia. FASEB J.14, 1861–1863.10.1096/fj.99-1011fjeSearch in Google Scholar
Renne, T., Pozgajova, M., Gruner, S., Schuh, K., Pauer, H.U., Burfeind, P., Gailani, D., and Nieswandt, B. (2005). Defective thrombus formation in mice lacking coagulation factor XII. J. Exp. Med.202, 271–281.10.1084/jem.20050664Search in Google Scholar
Rhaleb, N.E., Yang, X.P., Nanba, M., Shesely, E.G., and Carretero, O.A. (2001). Effect of chronic blockade of the kallikrein-kinin system on the development of hypertension in rats. Hypertension37, 121–128.10.1161/01.HYP.37.1.121Search in Google Scholar
Ribeiro, J.M., Santos, R.A., Pesquero, J.B., Bader, M., and Krieger, E.M. (2005). Autonomic control in rats with overactivity of tissue renin-angiotensin or kallikrein-kinin system. Regul. Pept.129, 155–159.10.1016/j.regpep.2005.02.009Search in Google Scholar
Rupniak, N.M., Boyce, S., Webb, J.K., Williams, A.R., Carlson, E.J., Hill, R.G., Borkowski, J.A., and Hess, J.F. (1997). Effects of the bradykinin B1 receptor antagonist des-Arg9[Leu8]bradykinin and genetic disruption of the B2 receptor on nociception in rats and mice. Pain71, 89–97.10.1016/S0304-3959(97)03343-5Search in Google Scholar
Sainz, I.M., Isordia-Salas, I., Castaneda, J.L., Agelan, A., Liu, B., DeLa Cadena, R.A., Pixley, R.A., Adam, A., Sartor, R.B., and Colman, R.W. (2005). Modulation of inflammation by kininogen deficiency in a rat model of inflammatory arthritis. Arthritis Rheum.52, 2549–2552.10.1002/art.21202Search in Google Scholar PubMed
Samadfam, R., Teixeira, C., Bkaily, G., Sirois, P., Brum-Fernandes, A., and D'Orleans-Juste, P. (2000). Contribution of B2 receptors for bradykinin in arthus reaction-induced plasma extravasation in wild-type or B2 transgenic knockout mice. Br. J. Pharmacol.129, 1732–1738.10.1038/sj.bjp.0703225Search in Google Scholar PubMed PubMed Central
Saria, A., Hauser, K.F., Traurig, H.H., Turbek, C.S., Hersh, L., and Gerard, C. (1997). Opioid-related changes in nociceptive threshold and in tissue levels of enkephalins after target disruption of the gene for neutral endopeptidase (EC 3.4.24.11) in mice. Neurosci. Lett.234, 27–30.10.1016/S0304-3940(97)00660-5Search in Google Scholar
Schanstra, J.P., Neau, E., Drogoz, P., Arevalo Gomez, M.A., Lopez Novoa, J.M., Calise, C., Pecher, C., Bader, M., Girolami, J.-P., and Bascands, J.-L. (2002). In vivo bradykinin B2-receptor activation reduces renal fibrosis. J. Clin. Invest.110, 371–379.10.1172/JCI0215493Search in Google Scholar
Schanstra, J.P., Duchene, J., Praddaude, F., Bruneval, P., Tack, I., Chevalier, J., Girolami, J.P., and Bascands, J.L. (2003). Decreased renal NO excretion and reduced glomerular tuft area in mice lacking the bradykinin B2 receptor. Am. J. Physiol. Heart Circ. Physiol.284, H1904–H1908.10.1152/ajpheart.01150.2002Search in Google Scholar
Shariat-Madar, Z., Mahdi, F., and Schmaier, A.H. (2002). Identification and characterization of prolylcarboxypeptidase as an endothelial cell prekallikrein activator. J. Biol. Chem.277, 17962–17969.10.1074/jbc.M106101200Search in Google Scholar
Siems, W., Maul, B., Krause, W., Gerard, C., Hauser, K.F., Hersh, L.B., Fischer, H.S., Zernig, G., and Saria, A. (2000). Neutral endopeptidase and alcohol consumption, experiments in neutral endopeptidase-deficient mice. Eur. J. Pharmacol.397, 327–334.10.1016/S0014-2999(00)00222-3Search in Google Scholar
Silva, J.A. Jr., Araujo, R.C., Baltatu, O., Oliveira, S.M., Tschöpe, C., Fink, E., Hoffmann, S., Plehm, R., Chai, K.X., Chao, L., et al. (2000). Reduced cardiac hypertrophy and altered blood pressure control in transgenic rats with the human tissue kallikrein gene. FASEB J.14, 1858–1860.10.1096/fj.99-1010fjeSearch in Google Scholar PubMed
Souza, D.G., Lomez, E.S.L., Pinho, V., Pesquero, J.B., Bader, M., Pesquero, J.L., and Teixeira, M.M. (2004). Role of bradykinin B2 and B1 receptors in the local, remote, and systemic inflammatory responses that follow intestinal ischemia and reperfusion injury. J. Immunol.172, 2542–2548.10.4049/jimmunol.172.4.2542Search in Google Scholar PubMed
Sturiale, S., Barbara, G., Qiu, B., Figini, M., Geppetti, P., Gerard, N., Gerard, C., Grady, E.F., Bunnett, N.W., and Collins, S.M. (1999). Neutral endopeptidase (EC 3.4.24.11) terminates colitis by degrading substance P. Proc. Natl. Acad. Sci. USA96, 11653–11658.Search in Google Scholar
Todorov, A.D., Andrade, D., Pesquero, J.B., Araujo, R.C., Bader, M., Stewart, J., Gera, L., Müller-Esterl, W., Morandi, V., Coeli, R., et al. (2003). Trypanosoma cruzi induces edematogenic responses in mice and invades cardiomyocytes and endothelial cells in vitro by activating distinct kinin-receptor (B1/B2) subtypes. FASEB J.17, 73–75.10.1096/fj.02-0477fjeSearch in Google Scholar PubMed
Trabold, F., Pons, S., Hagege, A.A., Bloch-Faure, M., Alhenc-Gelas, F., Giudicelli, J.F., Richer-Giudicelli, C., and Meneton, P. (2002). Cardiovascular phenotypes of kinin B2 receptor- and tissue kallikrein-deficient mice. Hypertension40, 90–95.10.1161/01.HYP.0000021747.43346.95Search in Google Scholar PubMed
Tschöpe, C., Spielmann, F., Rehfeld, U., Koch, M., Westermann, D., Paul, M., Bader, M., Schultheiss, H.P., and Vetter, R. (2004a). Improvement of defective sarcoplasmic reticulum Ca2+ transport in diabetic heart of transgenic rats expressing the human kallikrein-1 gene. FASEB J.18, 1967–1969.10.1096/fj.04-1614fjeSearch in Google Scholar PubMed
Tschöpe, C., Walther, T., Königer, J., Spillmann, F., Westermann, D., Escher, F., Pauschinger, M., Pesquero, J.B., Bader, M., Schultheiss, H.P., and Noutsias, M. (2004b). Prevention of cardiac fibrosis and left ventricular dysfunction in diabetic cardiomyopathy in rats by transgenic expression of the human tissue kallikrein gene. FASEB J.18, 828–835.10.1096/fj.03-0736comSearch in Google Scholar PubMed
Tschöpe, C., Walther, T., Escher, F., Spillmann, F., Du, J., Altmann, C., Schimke, I., Bader, M., Sanchez-Ferrer, C.F., Schultheiss, H.P., and Noutsias, M. (2005). Transgenic activation of the kallikrein-kinin system inhibits intramyocardial inflammation, endothelial dysfunction and oxidative stress in experimental diabetic cardiomyopathy. FASEB J.19, 2057–2059.10.1096/fj.05-4095fjeSearch in Google Scholar PubMed
Ueno, A. and Ohishi, S. (2003). Roles for the kallikrein-kinin system in inflammatory exudation and pain: lessons from studies on kininogen-deficient rats. J. Pharmacol. Sci.93, 1–20.10.1254/jphs.93.1Search in Google Scholar PubMed
Vickers, C., Hales, P., Kaushik, V., Dick, L., Gavin, J., Tang, J., Godbout, K., Parsons, T., Baronas, E., Hsieh, F., et al. (2002). Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J. Biol. Chem.277, 14838–14843.10.1074/jbc.M200581200Search in Google Scholar PubMed
Wang, D., Yoshida, H., Song, Q., Chao, L., and Chao, J. (2000). Enhanced renal function in bradykinin B2 receptor transgenic mice. Am. J. Physiol. Renal Physiol.278, F484–F491.10.1152/ajprenal.2000.278.3.F484Search in Google Scholar PubMed
Wang, D.Z., Chao, L., and Chao, J. (1997). Hypotension in transgenic mice overexpressing human bradykinin B2 receptor. Hypertension29, 488–493.10.1161/01.HYP.29.1.488Search in Google Scholar PubMed
Wang, J., Xiong, W., Yang, Z., Davis, T., Dewey, M.J., Chao, J., and Chao, L. (1994). Human tissue kallikrein induces hypotension in transgenic mice. Hypertension23, 236–243.10.1161/01.HYP.23.2.236Search in Google Scholar PubMed
Xiao, H.D., Fuchs, S., Cole, J.M., Disher, K.M., Sutliff, R.L., and Bernstein, K.E. (2003). Role of bradykinin in angiotensin-converting enzyme knockout mice. Am. J. Physiol. Heart Circ. Physiol.284, H1969–H1977.10.1152/ajpheart.00010.2003Search in Google Scholar PubMed
Yang, X.P., Liu, Y.H., Scicli, G.M., Webb, C.R., and Carretero, O.A. (1997). Role of kinins in the cardioprotective effect of preconditioning: study of myocardial ischemia/reperfusion injury in B2 kinin receptor knockout mice and kininogen-deficient rats. Hypertension30, 735–740.10.1161/01.HYP.30.3.735Search in Google Scholar PubMed
Yu, H., Song, Q., Freedman, B.I., Chao, J., Chao, L., Rich, S.S., and Bowden, D.W. (2002). Association of the tissue kallikrein gene promoter with ESRD and hypertension. Kidney Int.61, 1030–1039.10.1046/j.1523-1755.2002.00198.xSearch in Google Scholar PubMed
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