Kinins

This handbook of kinin biology and biochemistry covers the current knowledge of kinins, a family of peptides involved in numerous physiological and pathophysiological processes. Recent publications have shown that the kinin system is highly relevant in a variety of disease states such as diabetes, multiple sclerosis and traumatic injuries. Furthermore, the first drug targeting system has just been approved for clinical use. The goal of this book is to provide advanced students and researchers a basic understanding of the kinin system and its role within the various organ systems. The authors of this book are experts in their fields, including a Nobel Laureate. * An important system in diseases such as diabetes, multiple sclerosis, as well as traumatic injuries * Handbook organized by organ systems for easy reference * Full colour illustrations Kinins......Page 4 Preface......Page 6 Contributors......Page 8 Contents......Page 12 1 Kinins: History and outlook......Page 18 References......Page 20 2.2 Kinins and kininogens......Page 24 2.3 Kallikreins......Page 27 2.4 Kininases......Page 31 2.5 Kinin receptors......Page 35 2.6 Genetics of the kallikrein-kinin system......Page 36 References......Page 39 3.3 Kinin binding sites in the receptors......Page 50 3.4 Receptor maturation and cellular distribution......Page 51 3.5.1 Agonist-stimulated receptor signaling......Page 52 3.5.3 Roles of proteases in receptor signaling......Page 54 3.6.1 Receptor gene regulation......Page 55 3.6.3 Receptor trafficking......Page 57 References......Page 59 4.2 Animal models for the study of kinins......Page 68 4.3.1 B1 receptor knockout models......Page 69 4.3.2 B1R overexpression models......Page 72 4.3.3 Models of tissue-specific expression of B1 receptor......Page 73 4.4 B2 receptor transgenic models......Page 74 4.5 B1 and B2 receptor knockout model......Page 77 References......Page 80 5.2 Plasma kallikrein inhibitors......Page 86 5.4 B2R antagonists......Page 88 5.5 B2R agonists......Page 91 5.6 B1R antagonists......Page 92 5.8 ACE inhibitors......Page 93 5.10 Other considerations......Page 94 References......Page 95 6.2 Kallikrein-kinin system and kinins in neural tissue and brain......Page 102 6.2.2 Kallikrein levels......Page 103 6.3.1 Expression of kinin receptors and their functions in the brain......Page 104 6.3.2 Kinin receptors and their functions in astrocytes......Page 105 6.3.3 Kinin receptors and their functions in microglia......Page 106 6.4.1 Memory impairment in AD and BK receptors......Page 108 6.4.2 Epilepsy and kinin receptors......Page 110 6.4.4 Hypertension and kinin receptors in the brain......Page 111 6.4.5 Kinins and brain infl ammation......Page 112 References......Page 113 7.1.3 Kinin receptors......Page 120 7.2 Kidney development......Page 121 7.3.1 Renal blood flow......Page 122 7.3.2 Urinary excretion......Page 123 7.5 Glomerular injury......Page 124 7.6 Tubulointerstitial fibrosis......Page 125 References......Page 127 8.2 The local cardiac KKS under physiological conditions......Page 134 8.3.1 The local cardiac KKS......Page 135 8.3.3 The influence of the KKS on endothelial dysfunction and inflammation......Page 136 8.3.4 The influence of the KKS on the extracellular matrix......Page 137 8.3.5 The effects of the KKS on intracellular Ca2+ -handling......Page 138 8.3.6 The KKS and angiogenesis......Page 139 8.4.2 The role of the KKS on cardiac left ventricular remodeling......Page 140 8.5 The role of the KKS in post ischemic angiogenesis, neovascularization, and stem cell recruitment......Page 143 References......Page 144 9.2.1 Developmental expression of the KKS......Page 154 9.2.3 Insights from genetically modifi ed animals......Page 156 9.3 The rise and plunge of vasodilatory theory: a suspended verdict......Page 157 9.4 Involvement of the KKS in vessel growth......Page 158 9.5 Involvement of the KKS in atherosclerotic vessel wall remodeling and vascular repair......Page 160 References......Page 162 10.1 The skin: a defensive barrier......Page 172 10.2 Kallikreins, kinins, and kinin receptors in the skin......Page 173 10.3.1 Cell differentiation and skin desquamation......Page 174 10.3.2 Contribution of kallikreins to innate immunity and wound healing......Page 176 10.4 Kinin receptors and EGFR transactivation......Page 177 10.5 Kinin receptors and keratinocyte differentiation......Page 178 References......Page 181 11.2.1 Two pathways for kinin production......Page 188 11.3.1 Localization of KKS components in ocular structure......Page 190 11.4.1 Retinal vascular functions......Page 192 11.4.2 Neuroretinal functions......Page 194 11.4.3 Aqueous outflow facility......Page 195 11.4.6 Ciliary artery dilatation......Page 196 11.5.2 Diabetic macular edema......Page 197 Acknowledgments......Page 198 References......Page 199 12.2.1 Kininogens......Page 204 12.2.2 Kallikrein-related peptidases......Page 205 12.2.3 Bradykinin receptor......Page 206 12.2.4 Kininases......Page 209 12.2.5 Involvement of the KKS in the physiology of male reproductive organs......Page 210 12.3.2 Kallikrein-related peptidases......Page 212 12.3.5 Involvement of the KKS in the physiology of female reproductive organs......Page 213 References......Page 214 13.2 Plasmatic coagulation......Page 220 13.3 FXII and the intrinsic pathway of blood coagulation......Page 221 13.4 Deficiency in contact factors protects from thrombosis......Page 223 13.5 Role of contact factors for thromboembolic disease in humans......Page 224 13.6 Putting the contact into contact activation......Page 226 13.7 Polyphosphates: the endogenous activator of FXII in thrombosis......Page 227 References......Page 229 14.2.1 Classical kallikreins......Page 234 14.2.3 Kinins......Page 235 14.2.4 Kinin receptors......Page 236 14.3 The kinin system and tumor microenvironment......Page 237 14.4.1 Mitogenic kinins......Page 239 14.4.2 Kinin receptors......Page 240 14.4.3 Kinin receptor antagonists......Page 241 14.5 True tissue kallikrein and kinin receptors in human tumors......Page 242 14.5.1 Breast cancer......Page 243 14.5.2 Glioblastoma......Page 246 14.5.3 Astrocytomas......Page 247 14.5.5 Prostate cancer......Page 248 14.5.7 Esophageal and gastric cancer......Page 249 14.5.11 Chondrosarcoma......Page 250 14.6 Kallikrein-related peptidases (KLK2-KLK15/hK2-KLK15)......Page 251 References......Page 252 15.1 Introduction......Page 264 15.2 Kinins and infl ammatory pain......Page 265 15.3 Kinins and visceral pain......Page 267 15.4 Kinins and neuropathic pain......Page 268 15.5 Kinins and cancer/chemotherapy pain......Page 270 15.6 Kinins and itch......Page 271 References......Page 272 16.1 Introduction......Page 278 16.2 The KKS in inflammation......Page 279 16.3 B2R and the initiation of inflammation......Page 280 16.4 B1R and the progression of inflammation......Page 282 16.5 B1R and monocytes/macrophages......Page 284 16.6 KKS and the adaptive immune response......Page 285 References......Page 286 17.2.1 ACE and diabetic nephropathy......Page 290 17.2.2 Kinin receptors and diabetic nephropathy......Page 292 17.4 KKS and diabetic neuropathy......Page 294 17.6 Nitric oxide mediates the beneficial effect of KKS on diabetic complications......Page 295 17.7 Role of oxidative metabolism in preventing diabetic complications by KKS......Page 296 17.8 Therapeutic implications......Page 297 References......Page 298 18.1.1.1 Angioedema not responsive to antihistamine......Page 306 18.1.1.2 Angioedema due to C1-inhibitor deficiency......Page 307 18.1.1.4 Idiopathic non-histaminergic angioedema......Page 308 18.2.1 C1-inhibitor deficiency and the generation of bradykinin......Page 309 18.2.1.2 Pathophysiology of angioedema due to C1-inhibitor deficiency......Page 311 18.2.2 ACE inhibitors and the catabolism of bradykinin......Page 312 18.2.3 Bradykinin involvement in idiopathic angioedema......Page 313 18.3.1 C1-inhibitor replacement......Page 314 18.3.2 Kallikrein inhibition......Page 315 18.3.4 Inhibition of the fibrinolytic system......Page 316 References......Page 317 19.2 Kinin release by microorganisms......Page 324 19.3.1 Activation of FXII or PK......Page 325 19.3.2 Release from kininogens......Page 327 19.4 Kinin release at the surface of the microorganism......Page 328 19.5.1 Degradation of kinins by microorganisms......Page 329 19.6 Kinin receptor regulation......Page 330 19.7 Pathological consequences of kinin release by bacterial pathogens......Page 331 19.9 Concluding remarks......Page 332 References......Page 333 20.2.1 History and epidemiology of Chagas’ disease......Page 338 20.2.2 T. cruzi life cycle and the pathogenesis of Chagas’ disease......Page 339 20.2.3 T. cruzi expresses kinin -releasing cysteine proteases......Page 340 20.2.4 T. cruzi invades cardiovascular cells through the activation of kinin receptors......Page 341 20.2.5 Interstitial edema is orchestrated by a transcellular “cross-talk” between TLR2, CXCR2, and B2R......Page 342 20.2.6 Kinins steer TH1 polarization through the activation of dendritic cells......Page 345 20.2.7 Kinins orchestrate protective immune responses against systemic T. cruzi infection......Page 346 20.3.1 Leishmania life cycle and interplay with sand fly saliva......Page 347 20.3.3 Visceral leishmaniasis and the KKS......Page 348 References......Page 350 21.1 Introduction......Page 354 21.2.1 Kinin receptors......Page 356 21.2.2 Kallikreins and serine protease inhibitors......Page 360 21.2.3 Coagulation factor XII (FXII )......Page 362 21.3.1 Kinin receptors......Page 363 21.3.2 Kallikreins and serine protease inhibitors......Page 364 References......Page 365 Index......Page 372

This handbook of kinin biology and biochemistry covers the current knowledgeof kinins, a family of peptides involved in numerous physiological and pathophysiological processes. Recent publications have shown that the kinin system is highly relevant in a variety of disease states such as diabetes, multiple sclerosis and traumatic injuries. Furthermore, the first drug targeting system has just been approved for clinical use. The goal of this book is to provide advanced students and researchers a basic understanding of the kinin system and its role within the various organ systems.

The authors of this book are experts in their fields, including a Nobel Laureate.