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• W2010644436 abstract "Diabetic retinopathy and diabetic nephropathy are common microvascular complications of diabetes. The kallikrein–kinin system (KKS) has been implicated in the development of both conditions, and, in particular, bradykinin and its receptors have been shown to exert angiogenic and proinflammatory actions. Several of the key processes that underlie the development of diabetic retinopathy, such as increased vascular permeability, edema, neovascularization, and inflammatory changes, have been associated with the KKS, and recent work has shown that components of the KKS, including plasma kallikrein, factor XIIa, and high-molecular-weight kininogen, are present in the vitreous of people with diabetic retinopathy. The role of the KKS in the development of diabetic nephropathy is controversial, with both adverse and protective effects of bradykinin and its receptors reported. The review examines the role of the KKS in pathways central to the development of diabetic retinopathy and compares this with reported actions of this system in diabetic nephropathy. The possibility of therapeutic intervention targeting bradykinin and its receptors as treatment for diabetic microvascular conditions is considered. Diabetic retinopathy and diabetic nephropathy are common microvascular complications of diabetes. The kallikrein–kinin system (KKS) has been implicated in the development of both conditions, and, in particular, bradykinin and its receptors have been shown to exert angiogenic and proinflammatory actions. Several of the key processes that underlie the development of diabetic retinopathy, such as increased vascular permeability, edema, neovascularization, and inflammatory changes, have been associated with the KKS, and recent work has shown that components of the KKS, including plasma kallikrein, factor XIIa, and high-molecular-weight kininogen, are present in the vitreous of people with diabetic retinopathy. The role of the KKS in the development of diabetic nephropathy is controversial, with both adverse and protective effects of bradykinin and its receptors reported. The review examines the role of the KKS in pathways central to the development of diabetic retinopathy and compares this with reported actions of this system in diabetic nephropathy. The possibility of therapeutic intervention targeting bradykinin and its receptors as treatment for diabetic microvascular conditions is considered. Diabetic retinopathy is a leading cause of vision loss in working-age adults and this condition often occurs concurrently with diabetic nephropathy.1.Klein R. Zinman B. Gardiner R. et al.The relationship of diabetic retinopathy to preclinical diabetic glomerulopathy lesions in type 1 diabetic patients: the Renin–Angiotensin System Study.Diabetes. 2005; 54: 527-533Crossref PubMed Scopus (101) Google Scholar A growing body of evidence has implicated the kallikrein–kinin system (KKS) in the pathogenesis of both these microvascular complications of diabetes mellitus. Bradykinin (1–9) and its receptors, bradykinin receptors 1 (B1) and 2 (B2), are the primary effector pathway of the KKS and have been reported to exert both protective2.Chao J. Li H.J. Yao Y.Y. et al.Kinin infusion prevents renal inflammation, apoptosis, and fibrosis via inhibition of oxidative stress and mitogen-activated protein kinase activity.Hypertension. 2007; 49: 490-497Crossref PubMed Scopus (54) Google Scholar, 3.Kakoki M. Takahashi N. Jennette J.C. et al.Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor.Proc Natl Acad Sci USA. 2004; 101: 13302-13305Crossref PubMed Scopus (104) Google Scholar, 4.Kakoki M. McGarrah R.W. Kim H.S. et al.Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury.Proc Natl Acad Sci USA. 2007; 104: 7576-7581Crossref PubMed Scopus (100) Google Scholar and adverse5.Chiang W.C. Chien C.T. Lin W.W. et al.Early activation of bradykinin B2 receptor aggravates reactive oxygen species generation and renal damage in ischemia/reperfusion injury.Free Radic Biol Med. 2006; 41: 1304-1314Crossref PubMed Scopus (42) Google Scholar,6.Tan Y. Keum J.S. Wang B. et al.Targeted deletion of B2-kinin receptors protects against the development of diabetic nephropathy.Am J Physiol Renal Physiol. 2007; 293: F1026-F1035Crossref PubMed Scopus (43) Google Scholar effects on the kidney. Studies using B2 receptor-deficient mice with diabetes have shown both increased3.Kakoki M. Takahashi N. Jennette J.C. et al.Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor.Proc Natl Acad Sci USA. 2004; 101: 13302-13305Crossref PubMed Scopus (104) Google Scholar and decreased6.Tan Y. Keum J.S. Wang B. et al.Targeted deletion of B2-kinin receptors protects against the development of diabetic nephropathy.Am J Physiol Renal Physiol. 2007; 293: F1026-F1035Crossref PubMed Scopus (43) Google Scholar glomerular injury compared with diabetic wild-type controls. Recently, we have reported that activation of plasma kallikrein in the vitreous can increase retinal vascular permeability, and in the presence of diabetes cause retinal edema.7.Gao B.B. Clermont A. Rook S. et al.Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation.Nat Med. 2007; 13: 181-188Crossref PubMed Scopus (236) Google Scholar Indeed, bradykinin has been shown to exert both proinflammatory and proangiogenic effects that are central to the pathogenesis of sight-threatening proliferative diabetic retinopathy (PDR) and diabetic macular edema. As the KKS may provide therapeutic targets for both diabetic retinopathy and diabetic nephropathy, further understanding of the actions of this system in the pathogenesis of retinal and renal injury in diabetes is critical. We review the role of the KKS in pathways that are fundamental to the development of diabetic retinopathy, namely increased vascular permeability, neovascularization, and inflammation, and consider the possibility of therapeutic intervention targeting plasma kallikrein and bradykinin receptors as treatment for this condition. The actions of the KKS are primarily mediated by bradykinin (1–9), a peptide hormone that exerts potent proinflammatory and vasodilatory effects through the activation of two cell surface G-protein-coupled receptors: B1 receptor and B2 receptor (Figure 1). The half-life of bradykinin in plasma is short (27±10 s),8.Cyr M. Lepage Y. Blais Jr, C. et al.Bradykinin and des-Arg(9)-bradykinin metabolic pathways and kinetics of activation of human plasma.Am J Physiol Heart Circ Physiol. 2001; 281: H275-H283PubMed Google Scholar suggesting that its actions are regulated locally through its production and proteolytic processing within tissues. The generation of bradykinin is mediated by both plasma and tissue kallikreins, which are serine proteases that differ in their distribution and regulation. Human tissue kallikreins are a subgroup of 15 homologous secreted trypsin or chymotrypsin-like serine proteases (hK1 to hK15) encoded on chromosome 19q13.4.9.Madeddu P. Emanueli C. El Dahr S. Mechanisms of disease: the tissue kallikrein–kinin system in hypertension and vascular remodeling.Nat Clin Pract Nephrol. 2007; 3: 208-221Crossref PubMed Scopus (82) Google Scholar hK1 is the only member of the family that forms bradykinin and lys-bradykinin (kallidin) through its cleavage by low-molecular-weight kininogen. The production of bradykinin by tissue kallikrein is inhibited by protease inhibitors, such as kallistatin9.Madeddu P. Emanueli C. El Dahr S. Mechanisms of disease: the tissue kallikrein–kinin system in hypertension and vascular remodeling.Nat Clin Pract Nephrol. 2007; 3: 208-221Crossref PubMed Scopus (82) Google Scholar (Figure 1). Plasma kallikrein is encoded by a single gene localized on human gene 4q35 and is synthesized primarily in the liver. Plasma kallikrein is an abundant enzyme (35–50 μg ml−1) in plasma, and its activity is acutely increased by contact with negatively charged surfaces. This results in the cleavage of its substrates, factor XII (FXII) to factor XIIa (FXIIa), initiating the positive feedback mechanism of contact system activation, and high-molecular-weight kininogen (HK), resulting in the release of bradykinin (Figure 1). Although the physiological mechanisms that activate plasma kallikrein are not fully understood, we have recently demonstrated that plasma kallikrein can also be activated by a modest increase in pH, induced by extracellular carbonic anhydrase.7.Gao B.B. Clermont A. Rook S. et al.Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation.Nat Med. 2007; 13: 181-188Crossref PubMed Scopus (236) Google Scholar The primary physiological inhibitors of plasma kallikrein are complement 1 inhibitor (C1-INH) and α-2 macroglobulin.10.Joseph K. Kaplan A.P. Formation of bradykinin: a major contributor to the innate inflammatory response.Adv Immunol. 2005; 86: 159-208Crossref PubMed Scopus (108) Google Scholar C1-INH is also a primary physiological inhibitor of FXIIa, and thereby an inhibitor of plasma kallikrein activation. The relative contributions of plasma and tissue kallikrein isoenzymes to bradykinin production and the downstream consequences of bradykinin actions are likely different in the retina and kidney. Although tissue kallikrein mRNA has been detected in human retina,11.Ma J.X. Song Q. Hatcher H.C. et al.Expression and cellular localization of the kallikrein–kinin system in human ocular tissues.Exp Eye Res. 1996; 63: 19-26Crossref PubMed Scopus (80) Google Scholar its role in retinal physiology is unknown. Tissue kallikrein activity appears very low to undetectable in vitreous of people with PDR.12.Pinna A. Emanueli C. Dore S. et al.Levels of human tissue kallikrein in the vitreous fluid of patients with severe proliferative diabetic retinopathy.Ophthalmologica. 2004; 218: 260-263Crossref PubMed Scopus (9) Google Scholar Intravitreal injection of a tissue kallikrein inhibitor, kallistatin, in rats with streptozotocin (STZ)-induced diabetes reduced retinal neovascularization; however, these effects have been attributed to the effects on the VEGF system.13.Gao G. Shao C. Zhang S.X. et al.Kallikrein-binding protein inhibits retinal neovascularization and decreases vascular leakage.Diabetologia. 2003; 46: 689-698PubMed Google Scholar In contrast, we have recently demonstrated that vitreous fluid from people with PDR contains contact system proteins, including plasma kallikrein, FXII, and HK.7.Gao B.B. Clermont A. Rook S. et al.Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation.Nat Med. 2007; 13: 181-188Crossref PubMed Scopus (236) Google Scholar These findings suggest that the plasma kallikrein system could play an important role in regulating the intraocular KKS in diabetic retinopathy. As these contact system components are highly abundant in the plasma, we have proposed that these proteins reach the retinal interstitium and vitreous by crossing the blood–retinal barrier through increased vascular permeability and retinal hemorrhage, which are hallmarks of diabetic retinopathy (Figure 2). In the kidney, disruption of the tissue kallikrein (KlK1) gene dramatically reduces renal kinin production,14.Meneton P. Bloch-Faure M. Hagege A.A. et al.Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice.Proc Natl Acad Sci USA. 2001; 98: 2634-2639Crossref PubMed Scopus (134) Google Scholar suggesting that tissue kallikrein is the main bradykinin-generating enzyme in the kidney. Little is known regarding the potential role of plasma kallikrein and the contact system on renal function and diabetic nephropathy. In diabetes, renal kallikein levels and excretion of urinary kallikrein are decreased.15.Harvey J.N. Jaffa A.A. Margolius H.S. et al.Renal kallikrein and hemodynamic abnormalities of diabetic kidney.Diabetes. 1990; 39: 299-304Crossref PubMed Scopus (49) Google Scholar Although the intrarenal KKS has been implicated in contributing to diabetic nephropathy,16.Riad A. Zhuo J.L. Schultheiss H.P. et al.The role of the renal kallikrein–kinin system in diabetic nephropathy.Curr Opin Nephrol Hypertens. 2007; 16: 22-26Crossref PubMed Scopus (32) Google Scholar both beneficial and detrimental actions of bradykinin have been described.3.Kakoki M. Takahashi N. Jennette J.C. et al.Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor.Proc Natl Acad Sci USA. 2004; 101: 13302-13305Crossref PubMed Scopus (104) Google Scholar,6.Tan Y. Keum J.S. Wang B. et al.Targeted deletion of B2-kinin receptors protects against the development of diabetic nephropathy.Am J Physiol Renal Physiol. 2007; 293: F1026-F1035Crossref PubMed Scopus (43) Google Scholar The downstream biological effects of the KKS are primarily mediated by B2 and B1 receptors, which are widely expressed in vascular tissues, including in the retina.11.Ma J.X. Song Q. Hatcher H.C. et al.Expression and cellular localization of the kallikrein–kinin system in human ocular tissues.Exp Eye Res. 1996; 63: 19-26Crossref PubMed Scopus (80) Google Scholar The B2 receptor is constitutively expressed in many vascular and neuronal tissues, whereas the B1 receptor is inducible and has been attributed to many of the proinflammatory actions of bradykinin.17.Schanstra J.P. Bataille E. Marin Castano M.E. et al.The B1-agonist [des-Arg10]-kallidin activates transcription factor NF-kappaB and induces homologous upregulation of the bradykinin B1-receptor in cultured human lung fibroblasts.J Clin Invest. 1998; 101: 2080-2091Crossref PubMed Scopus (164) Google Scholar,18.Sabourin T. Morissette G. Bouthillier J. et al.Expression of kinin B(1) receptor in fresh or cultured rabbit aortic smooth muscle: role of NF-kappa B.Am J Physiol Heart Circ Physiol. 2002; 283: H227-H237Crossref PubMed Scopus (42) Google Scholar Activation of these receptors stimulate potent vasoactive mediators, such as endothelial nitric oxide synthase (eNOS), leading to the increased production of nitric oxide (NO), cyclic GMP, and prostacyclin.19.Vanhoutte P.M. Boulanger C.M. Mombouli J.V. Endothelium-derived relaxing factors and converting enzyme inhibition.Am J Cardiol. 1995; 76: 3E-E12Abstract Full Text PDF PubMed Scopus (129) Google Scholar Plasma kallikrein has also been shown to mediate plasminogen activation to plasmin,20.Selvarajan S. Lund L.R. Takeuchi T. et al.A plasma kallikrein-dependent plasminogen cascade required for adipocyte differentiation.Nat Cell Biol. 2001; 3: 267-275Crossref PubMed Scopus (125) Google Scholar which mediates both fibrinolysis and the activation of matrix metalloproteinases. These findings suggest that the KKS may exert effects on vascular homeostasis through bradykinin receptor-independent mechanisms. The consequences of these kallikrein and bradykinin actions could have critical differences in regard to the pathogenic mechanisms contributing to diabetic retinopathy and nephropathy. Bradykinin is rapidly metabolized by a number of kininases, including the angiotensin-converting enzyme (ACE), also known as kininase II, and neural endopeptidase 24.11, a kininase that is abundant in the kidney. Kininase I-type carboxypeptidases convert bradykinin into [des-Arg9]-bradykinin, which exerts its maximal effect through the B1 receptor.21.Madeddu P. Emanueli C. El Dahr S. Mechanisms of disease: the tissue kallikrein–kinin system in hypertension and vascular remodeling.Nat Clin Pract Nephrol. 2007; 3: 208-221Crossref PubMed Scopus (61) Google Scholar In acquired angioedema, ACE inhibition can increase circulating concentrations of bradykinin,22.Nussberger J. Cugno M. Amstutz C. et al.Plasma bradykinin in angio-oedema.Lancet. 1998; 351: 1693-1697Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar confirming the importance of ACE-mediated proteolysis in the KKS. Indeed, the beneficial effects of ACE inhibitors have been attributed to both the inhibition of angiotensin II production and the reduction of bradykinin breakdown. Thus, bradykinin concentrations and actions in the retina and kidney could potentially be regulated at the level of bradykinin proteolysis. Diabetic retinopathy is primarily considered a vascular disease; however, involvement of the neuroretina is also evident.23.Antonetti D.A. Barber A.J. Bronson S.K. et al.Diabetic retinopathy: seeing beyond glucose-induced microvascular disease.Diabetes. 2006; 55: 2401-2411Crossref PubMed Scopus (568) Google Scholar The initial stages of diabetic retinopathy include changes in blood flow and vessel diameters, as well as the development of microaneurysms and retinal hemorrhages (reviewed in Frank24.Frank R.N. Diabetic retinopathy.N Engl J Med. 2004; 350: 48-58Crossref PubMed Scopus (858) Google Scholar). Microvascular changes, such as basement membrane thickening, pericyte loss, leukostasis, and increased retinal vascular permeability, also occur early in the disease progression.25.Chakrabarti S. Cukiernik M. Hileeto D. et al.Role of vasoactive factors in the pathogenesis of early changes in diabetic retinopathy.Diabetes Metab Res Rev. 2000; 16: 393-407Crossref PubMed Scopus (85) Google Scholar The presence of increased vascular permeability and leukostasis suggests that retinal inflammation plays a role in the pathogenesis of diabetic retinopathy, and indeed inflammatory changes are noted early following the onset of diabetes in the vasculature of insulin-deficient diabetic rats.26.Kern T.S. Miller C.M. Du Y. et al.Topical administration of nepafenac inhibits diabetes-induced retinal microvascular disease and underlying abnormalities of retinal metabolism and physiology.Diabetes. 2007; 56: 373-379Crossref PubMed Scopus (130) Google Scholar Increased retinal vascular permeability can progress and contribute to the development of macular edema, one of the most common causes of vision loss in diabetic retinopathy. The primary cause of macular edema is thought to involve the breakdown of the blood–retinal barrier, causing leakage of plasma from small blood vessels into the central portion of the retina and subsequent intraretinal swelling.24.Frank R.N. Diabetic retinopathy.N Engl J Med. 2004; 350: 48-58Crossref PubMed Scopus (858) Google Scholar In addition, diabetic retinopathy can cause areas of reduced vascular perfusion, which can lead to retinal hypoxia and trigger neovascularization.24.Frank R.N. Diabetic retinopathy.N Engl J Med. 2004; 350: 48-58Crossref PubMed Scopus (858) Google Scholar This response is one of the hallmarks of the most severe forms of the disease, PDR, which can lead to vitreous hemorrhage, retinal detachment, and severe vision loss. Our recent studies have shown that activation of the intraocular KKS can increase retinal vascular permeability in rats and, in the presence of diabetes, induce retinal edema.7.Gao B.B. Clermont A. Rook S. et al.Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation.Nat Med. 2007; 13: 181-188Crossref PubMed Scopus (236) Google Scholar This study extends previous findings that have shown antagonism of the B1 receptor ameliorates vascular leakage in the retina in rats with STZ-induced diabetes.27.Lawson S.R. Gabra B.H. Guerin B. et al.Enhanced dermal and retinal vascular permeability in streptozotocin-induced type 1 diabetes in Wistar rats: blockade with a selective bradykinin B1 receptor antagonist.Regul Pept. 2005; 124: 221-224Crossref PubMed Scopus (36) Google Scholar Moreover, these results are consistent with a large body of evidence that show bradykinin can increase vascular permeability, a response that has been demonstrated in a number of tissues. Indeed, bradykinin-induced vascular permeability is not a newly described phenomenon and was first reported several decades ago.28.Hulstrom D. Svensjo E. Intravital and electron microscopic study of bradykinin-induced vascular permeability changes using FITC-dextran as a tracer.J Pathol. 1979; 129: 125-133Crossref PubMed Scopus (80) Google Scholar Intravenous injections of bradykinin have been shown to increase the extravasation of 100 nM microspheres from tracheal venules in mice,29.Baffert F. Le T. Thurston G. et al.Angiopoietin-1 decreases plasma leakage by reducing number and size of endothelial gaps in venules.Am J Physiol Heart Circ Physiol. 2006; 290: H107-H118Crossref PubMed Scopus (112) Google Scholar giving an indication of the magnitude of bradykinin's effects on vascular permeability. In an experimental stroke model, ischemia/reperfusion injury induced by middle cerebral artery occlusion has been shown to increase local tissue bradykinin levels and B2 receptor expression, and cerebral edema induced by this injury is reduced in B2 receptor knockout mice compared with controls.30.Groger M. Lebesgue D. Pruneau D. et al.Release of bradykinin and expression of kinin B2 receptors in the brain: role for cell death and brain edema formation after focal cerebral ischemia in mice.J Cereb Blood Flow Metab. 2005; 25: 978-989Crossref PubMed Scopus (110) Google Scholar Bradykinin also induces leakage in postcapillary venules of rat mesentery through a B2 receptor-dependent mechanism, involving protein kinase C activation and cytochrome P450 epoxygenase.31.Shigematsu S. Ishida S. Gute D.C. et al.Bradykinin-induced proinflammatory signaling mechanisms.Am J Physiol Heart Circ Physiol. 2002; 283: H2676-H2686Crossref PubMed Scopus (25) Google Scholar In the retina, we have found that eNOS inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME) reduced retinal vascular permeability.7.Gao B.B. Clermont A. Rook S. et al.Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation.Nat Med. 2007; 13: 181-188Crossref PubMed Scopus (236) Google Scholar Bradykinin receptors have been shown to activate eNOS,32.Thuringer D. Maulon L. Frelin C. Rapid transactivation of the vascular endothelial growth factor receptor KDR/Flk-1 by the bradykinin B2 receptor contributes to endothelial nitric-oxide synthase activation in cardiac capillary endothelial cells.J Biol Chem. 2002; 277: 2028-2032Crossref PubMed Scopus (108) Google Scholar contributing to endothelium-dependent vasorelaxation. Although this pathway is generally considered vasoprotective, activation of eNOS can also contribute to increased vascular permeability,33.Bucci M. Roviezzo F. Posadas I. et al.Endothelial nitric oxide synthase activation is critical for vascular leakage during acute inflammation in vivo.Proc Natl Acad Sci USA. 2005; 102: 904-908Crossref PubMed Scopus (115) Google Scholar which can exert adverse effects in neurovascular tissues. These results indicate that bradykinin may increase vascular permeability through multiple mechanisms. Mechanisms involving the KKS in retinal vascular permeability may have parallels to the development of angioedema. The bradykinin pathway has been associated with both acquired and hereditary angioedema. Nussberger et al.22.Nussberger J. Cugno M. Amstutz C. et al.Plasma bradykinin in angio-oedema.Lancet. 1998; 351: 1693-1697Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar have shown that plasma bradykinin is elevated during angioedema attacks and that infusion with a C1-INH immediately lowers bradykinin levels. The involvement of the bradykinin pathway in acquired angioedema mediates, at least in part, the adverse effects of ACE inhibitors in this condition.22.Nussberger J. Cugno M. Amstutz C. et al.Plasma bradykinin in angio-oedema.Lancet. 1998; 351: 1693-1697Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar Han et al.34.Han E.D. MacFarlane R.C. Mulligan A.N. et al.Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor.J Clin Invest. 2002; 109: 1057-1063Crossref PubMed Scopus (288) Google Scholar demonstrated that B2 receptors are required for angioedema in C1-INH null mice. These findings suggest that C1-INH deficiency results in increased plasma kallikrein and FXIIa activities, which increase bradykinin production and promote B2 receptor-mediated vasogenic edema. Collectively, these findings using animal models suggest a pathway (plasma kallikrein → bradykinin → B2 → eNOS) contributing to vascular permeability and edema. Moreover, recent clinical trials have shown that the B2 receptor antagonist icatibant35.Bork K. Frank J. Grundt B. et al.Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant).J Allergy Clin Immunol. 2007; 119: 1497-1503Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar and the kallikrein inhibitor ecallantide36.Schneider L. Lumry W. Vegh A. et al.Critical role of kallikrein in hereditary angioedema pathogenesis: a clinical trial of ecallantide, a novel kallikrein inhibitor.J Allergy Clin Immunol. 2007; 120: 416-422Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar reduced symptoms in acute attacks of angioedema. Although the role of plasma kallikrein and the KKS in retinal vascular permeability in people with diabetic retinopathy is not yet available, the recent identification of plasma kallikrein, FXII, and HK in the vitreous of individuals with PDR7.Gao B.B. Clermont A. Rook S. et al.Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation.Nat Med. 2007; 13: 181-188Crossref PubMed Scopus (236) Google Scholar suggests that this pathway may contribute to retinal vascular permeability and edema in diabetic retinopathy. The development of new blood vessels is a hallmark of PDR. Although the role of the KKS in retinal neovascularization is not known, the proangiogenic effects of the KKS have been demonstrated in other tissues. The local delivery of bradykinin and B1 receptor-selective agonists stimulates angiogenesis in rabbit cornea.37.Parenti A. Morbidelli L. Ledda F. et al.The bradykinin/B1 receptor promotes angiogenesis by up-regulation of endogenous FGF-2 in endothelium via the nitric oxide synthase pathway.FASEB J. 2001; 15: 1487-1489Crossref PubMed Scopus (134) Google Scholar Moreover, bradykinin also induces neovascularization in the chicken chorioallantoic membrane assay.38.Colman R.W. Pixley R.A. Sainz I.M. et al.Inhibition of angiogenesis by antibody blocking the action of proangiogenic high-molecular-weight kininogen.J Thromb Haemost. 2003; 1: 164-170Crossref PubMed Scopus (63) Google Scholar HK promotes angiogenesis and may contribute to fibroblast growth factor 2 and vascular endothelial growth factor-induced angiogenesis through its cleavage by kallikrein to release bradykinin.38.Colman R.W. Pixley R.A. Sainz I.M. et al.Inhibition of angiogenesis by antibody blocking the action of proangiogenic high-molecular-weight kininogen.J Thromb Haemost. 2003; 1: 164-170Crossref PubMed Scopus (63) Google Scholar A neutralizing antibody against the light chain of HK, which interferes with the binding of HK to endothelial cells and thus blocks the cleavage of prekallikrein to kallikrein, inhibits tumor angiogenesis in a murine xenograft model.39.Song J.S. Sainz I.M. Cosenza S.C. et al.Inhibition of tumor angiogenesis in vivo by a monoclonal antibody targeted to domain 5 of high molecular weight kininogen.Blood. 2004; 104: 2065-2072Crossref PubMed Scopus (26) Google Scholar In models of angiogenesis induced by hind limb ischemia, the knockout of B1 receptor has been shown to impair new vessel growth, whereas a B1 receptor agonist increased the amount of neovascularization.40.Emanueli C. Bonaria S.M. Stacca T. et al.Targeting kinin B(1) receptor for therapeutic neovascularization.Circulation. 2002; 105: 360-366Crossref PubMed Scopus (110) Google Scholar In addition, the B2 receptor has also been implicated in angiogenesis.41.Ebrahimian T.G. Tamarat R. Clergue M. et al.Dual effect of angiotensin-converting enzyme inhibition on angiogenesis in type 1 diabetic mice.Arterioscler Thromb Vasc Biol. 2005; 25: 65-70PubMed Google Scholar These results suggest that the KKS contributes to ischemia-induced angiogenic responses. A limited number of studies suggest that the angiogenic response could be mediated by the upregulation of proangiogenic factors such as fibroblast growth factor 237.Parenti A. Morbidelli L. Ledda F. et al.The bradykinin/B1 receptor promotes angiogenesis by up-regulation of endogenous FGF-2 in endothelium via the nitric oxide synthase pathway.FASEB J. 2001; 15: 1487-1489Crossref PubMed Scopus (134) Google Scholar and through transactivation of the vascular endothelial growth factor-receptor 2 (Flk-1, KDR).32.Thuringer D. Maulon L. Frelin C. Rapid transactivation of the vascular endothelial growth factor receptor KDR/Flk-1 by the bradykinin B2 receptor contributes to endothelial nitric-oxide synthase activation in cardiac capillary endothelial cells.J Biol Chem. 2002; 277: 2028-2032Crossref PubMed Scopus (108) Google Scholar Although evidence for the direct activation of the vascular endothelial growth factor pathway by bradykinin in vivo is not yet available, therapeutic intervention targeting new blood vessel growth by modulating bradykinin action is intriguing. Retinal inflammation is involved in the development of diabetic retinopathy, with not only increases in vascular permeability, but also increases in leukostasis, superoxide, nuclear factor-κB, NO, cyclooxygenase 2, and prostaglandin-E2 seen in diabetic rat retinal microvessels.26.Kern T.S. Miller C.M. Du Y. et al.Topical administration of nepafenac inhibits diabetes-induced retinal microvascular disease and underlying abnormalities of retinal metabolism and physiology.Diabetes. 2007; 56: 373-379Crossref PubMed Scopus (130) Google Scholar Treatment of diabetic rats with topical nepafenac has been shown to ameliorate retinal inflammation and microvascular abnormalities, suggesting that these inflammatory pathways contribute to the pathogenesis of diabetic retinopathy.26.Kern T.S. Miller C.M. Du Y. et al.Topical administration of nepafenac inhibits diabetes-induced retinal microvascular disease and underlying abnormalities of retinal metabolism and physiology.Diabetes. 2007; 56: 373-379Crossref PubMed Scopus (130) Google Scholar Activation of the KKS has been shown to induce a host of proinflammatory responses. It has been reported that the B1 receptor expression is increased in the retina of rats with STZ-induced diabetes42.Abdouh M. Khanjari A. Abdelazziz N. et al.Early upregulation of kinin B1 receptors in retinal microvessels of the streptozotocin-diabetic rat.Br J Pharmacol. 2003; 140: 33-40Crossref PubMed Scopus (53) Google Scholar and that the activation of nuclear factor-κB upregulates B1 receptor expression.18.Sabourin T. Morissette G. Bouthillier J. et al.Expression of kinin B(1) receptor in fresh or cultured rabbit aortic smooth muscle: role of NF-kappa B.Am J Physiol Heart Circ Physiol. 2002; 283: H227-H237Crossref PubMed Scopus (42) Google Scholar Bradykinin has also been demonstrated to cause leukostasis,31.Shigematsu S. Ishida S. Gute D.C. et al.Bradykinin-induced proinflammatory signaling mechanisms.Am J Physiol Heart Circ Physiol. 2002; 283: H2676-H2686Crossref PubMed Scopus (25) Google Scholar,43.Bloechle C. Kusterer K. Kuehn R.M. et al.Inhibition of bradykinin B2 receptor preserves microcirculation in experimental pancreatitis in rats.Am J Physiol. 1998; 274: G42-G51PubMed Google Scholar possibly through a mechanism that involves bradykinin-induced superoxide formation.31.Shigematsu S. Ishida S. Gute D.C. et al.Bradykinin-induced proinflammatory signaling mechanisms.Am J Physiol Heart Circ Physiol. 2002; 283: H2676-H2686Crossref PubMed Scopus (25) Google Scholar Moreover, proinflammatory cytokines can upregulate the B1 receptor.44.Ni A. Chao L. Chao J. Transcription factor nuclear factor kappaB regulates the inducible expression of the human B1 receptor gene in inflammation.J Biol Chem. 1998; 273: 2784-2791Crossref PubMed Scopus (122) Google Scholar Expression of the B1 receptor is increased in lipopolysaccaride-induced vascular smooth muscle cells through a nuclear factor-κB-like nuclear factor.44.Ni A. Chao L. Chao J. Transcription factor nuclear factor kappaB regulates the inducible expression of the human B1 receptor gene in inflammation.J Biol Chem. 1998; 273: 2784-2791Crossref PubMed Scopus (122) Google Scholar An absence of B1 receptors results in decreased inflammatory responses to lipopolysaccaride, including a decrease in leukostasis,45.Pesquero J.B. Araujo R.C. Heppenstall P.A. et al.Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors.Proc Natl Acad Sci USA. 2000; 97: 8140-8145Crossref PubMed Scopus (318) Google Scholar and mice overexpressing the B1 receptor display increased susceptibility to paw edema,46.Ni A. Yin H. Agata J. et al.Overexpression of kinin B1 receptors induces hypertensive response to des-Arg9-bradykinin and susceptibility to inflammation.J Biol Chem. 2003; 278: 219-225Crossref PubMed Scopus (59) Google Scholar confirming that this receptor plays a central role in the initiation and modulation of inflammation. As the KKS is present in the vitreous from people with PDR, the proinflammatory effects of bradykinin and its receptors may contribute to retinal inflammation. The KKS, through activation of both B1 and B2 receptors, exerts a plethora of actions on vascular and neuronal tissues. In the eye, we have shown that the plasma KKS is present in the human vitreous from people with PDR and that this system can contribute to increased retinal vascular permeability in rodent models.7.Gao B.B. Clermont A. Rook S. et al.Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation.Nat Med. 2007; 13: 181-188Crossref PubMed Scopus (236) Google Scholar These findings are consistent with the well-documented effects of the KKS in vasogenic edema.22.Nussberger J. Cugno M. Amstutz C. et al.Plasma bradykinin in angio-oedema.Lancet. 1998; 351: 1693-1697Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar,34.Han E.D. MacFarlane R.C. Mulligan A.N. et al.Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor.J Clin Invest. 2002; 109: 1057-1063Crossref PubMed Scopus (288) Google Scholar Moreover, the KKS has been reported to contribute to angiogenesis and inflammation in a variety of tissues, suggesting that this system may also contribute to the proliferative ocular complications of diabetes. On the basis of these findings, the plasma KKS might provide a therapeutic target for diabetic macular edema and PDR. In diabetic nephropathy in mice, both beneficial and adverse effects of B2 receptor deficiency have been reported. B2 receptor deficiency has been shown to increase albumin excretion and glomerular mesangial sclerosis in mice with diabetes caused by the Akita mutation, Ins2+/C96Y.3.Kakoki M. Takahashi N. Jennette J.C. et al.Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor.Proc Natl Acad Sci USA. 2004; 101: 13302-13305Crossref PubMed Scopus (104) Google Scholar In contrast, Tan et al.6.Tan Y. Keum J.S. Wang B. et al.Targeted deletion of B2-kinin receptors protects against the development of diabetic nephropathy.Am J Physiol Renal Physiol. 2007; 293: F1026-F1035Crossref PubMed Scopus (43) Google Scholar recently demonstrated that deletion of the B2 receptor decreases glomerular and tubular injury and albumin excretion in mice made diabetic with STZ. A number of factors may contribute to the apparent differences in the role of the B2 receptor in diabetic nephropathy described in these reports, including differences in background genetics and the specific end points measured. Both studies, however, showed an increase in B1 receptor expression in diabetic B2 receptor knockouts, increased by approximately 10- and 25-fold in STZ diabetes and Akita-induced diabetes, respectively. At this time, it is not known whether B2 receptor deficiency selectively affects the B1 receptor or whether the absence of B2 receptors is associated with other expression abnormalities apart from the B1 receptor. Kakoki et al.4.Kakoki M. McGarrah R.W. Kim H.S. et al.Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury.Proc Natl Acad Sci USA. 2007; 104: 7576-7581Crossref PubMed Scopus (100) Google Scholar demonstrated that ischemia/reperfusion injury in mice deficient in both B1 and B2 receptors was worse than that observed in either B2 receptor-deficient or wild-type mice, demonstrating that both B1 and B2 receptors can affect ischemia/reperfusion injury. The protective effects of B1 and B2 receptor deficiency seem to contrast the results, demonstrating that stimulation of the B2 receptor by pretreatment with kallikrein worsens renal dysfunction in ischemia/reperfusion injury.5.Chiang W.C. Chien C.T. Lin W.W. et al.Early activation of bradykinin B2 receptor aggravates reactive oxygen species generation and renal damage in ischemia/reperfusion injury.Free Radic Biol Med. 2006; 41: 1304-1314Crossref PubMed Scopus (42) Google Scholar However, as both complete bradykinin receptor deficiency and overactivation of bradykinin receptors could potentially exert adverse effects, additional information is needed to identify the role and mechanisms of bradykinin action that are associated with the susceptibility to renal injury induced by diabetes or ischemia/reperfusion. On the basis of the findings of the KKS role in diabetic retinopathy, the potential effects of bradykinin on vascular permeability in the kidney warrant consideration. These results from both diabetic retinopathy and diabetic nephropathy indicate that the KKS plays a role in the microvascular complications of diabetes. Evaluation of the KKS as a potential therapeutic target for these complications will require additional information regarding the actions of specific kallikrein type (hK1 vs plasma kallikrein) and bradykinin receptors (B1 vs B2) on both the vascular functional abnormalities and histological changes associated with the pathogenesis of these conditions. Moreover, further understanding of the effects of bradykinin receptor-stimulated vasoactive substances, such as those of NO on intraglomerular pressure and retinal vascular permeability, will also need to be taken into consideration. Therefore, although components of the KKS might provide therapeutic targets for both diabetic retinopathy and diabetic nephropathy, further understanding of the systemic actions of this system is critical. This work was supported, in part, by the NHMRC Australia CJ Martin Research Fellowship (JAP), the US National Institutes of Health (Grant no. DK 60165), Juvenile Diabetes Research Foundation, and the Massachusetts Lions Eye Research Fund." @default.
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• W2010644436 title "The kallikrein–kinin system in diabetic retinopathy: Lessons for the kidney" @default.
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