Subject Index Aldosterone, plasminogen activator inhibitor-1 induction 163, 164, 168 Aminopeptidases angiotensin II processing 64 66, 214 diabetic expression 214, 215 Angiotensin I intrarenal compartmentalization 5 processing 72 salt effects on levels 2, 3 synthesis 1 Angiotensin II biological activity, overview 17, 241 243 cytokine actions 123 disease processes, see specific diseases inflammatory mediation, see Inflammation, angiotensin II mediation intrarenal compartmentalization interstitial fluid 5, 6 medulla vs cortex 5 origins 8 10 tubular compartmentalization 6 8, 48 intrarenal levels 2 4 obstructive nephropathy protection 116 120 peptides 1, 47, 63 66 processing 72 receptors, see AT1, AT2 regulation of levels 1 4, 10 renal autoregulation role 37, 38 renal growth factor activity fibroblast proliferation 102 glomerular endothelial cell proliferation 99, 100 history of study 97 loop of Henle cell proliferation 102 mesangial cell hypertrophy 99 organogenesis role 103, 104 overview 98 proximal tubular cell hypertrophy 100 102 renal hemodynamic effects, see Glomerular filtration rate, Renal blood flow, Tubuloglomerular feedback salt effects on levels 2, 3 tubular transport effects, see Collecting duct, Distal tubule, Loop of Henle, Macula densa, Proximal tubule Angiotensin III inflammatory mediation 132, 133, 142 processing 63 65, 132 Angiotensin IV AT4 receptor 66, 69, 162 exogenous effects 68 levels in renal disease 68 neutralization studies 69 pathogenesis role prerequisites 66 plasminogen activator inhibitor-1 induction 67, 162, 163 processing 63, 64 Angiotensin-converting enzyme chronic allograft dysfunction prevention 230 232 262
diabetic expression 213 gene polymorphism in chronic allograft dysfunction 227 knockout mouse phenotype 74, 76, 79 localization in atherosclerotic arteries 235 transforming growth factor- effects on synthesis 156 Angiotensin-converting enzyme inhibitors age-related sclerosis effects 166 antiinflammatory effects 142 AT1 antagonist combination therapy 208 atherosclerosis prevention studies Heart Outcomes Prevention Evaluation Study 206, 207, 239 QUIET study 239 SCAT study 239 TREND study 239 clinical trials of renal disease progression AIPRI trial 201, 202 Collaborative Study Group 200, 201 dosing 203, 204 REIN study 192, 193, 195, 202, 203 compliance 206 creatinine increase 204 diabetic nephropathy fibrosis trials 180, 181 fibrosis attenuation 63 glomerulosclerosis protection 165, 166 hemodynamic effects clinical renal disease 41 44 experimental renal insufficiency 39 41 hyperkalemia induction 205, 206 initiation of therapy 206, 209 mechanism of blood pressure reduction 47, 48 nephroprotection mechanisms 203 proteinuria effects animal studies 194 clinical trials 192 195 diabetic nephropathy 194, 195 renal growth attenuation 93 side effects 231 teratogenicity 114 unilateral ureteral obstruction effects 250 253 Angiotensinogen circulating levels 1 diabetic expression 214 intrarenal compartmentalization 9, 10 knockout mouse phenotype 74, 76 nuclear factor- B induction 141 Arteriole, exogenous angiotensin II effects on diameter 35 AT1 blockade effects age-related sclerosis effects 166 inhibitor combination therapy 208 chronic allograft dysfunction prevention 228 232 fibrosis attenuation 63, 82, 83, 156, 157 hemodynamics clinical renal disease 41 44 experimental renal insufficiency 39 41 mechanism of blood pressure reduction 47 nephroprotection studies 207, 208 obstructive nephropathy 118, 119 side effects 231 sodium excretion 37 developmental expression 103 diabetic expression 213, 214 endocytosis of ligand complex 5 functional effects of activation 17, 73 kidney distribution 49, 161 knockout mouse phenotypes blood pressure 76 78 cardiac ischemia-reperfusion injury model 85 developmental effects 75, 76 hydronephrosis in newborns 112, 113 interstitial renal fibrosis model 83 left ventricular hypertrophy model 84, 85 mixed lymphocyte response 85, 86 renal hemodynamics 79 renal pelvis growth 113 116 sodium balance 80, 81 tubuloglomerular feedback 79, 80 water homeostasis 81, 82 nuclear factor- B activation 129, 131 Subject Index 263
AT1 (continued) rodent genes 17, 18, 49, 73 signaling c-fos expression studies 27 clinical application of studies 31 Fyn 26, 27, 29 G protein-coupled receptors 18, 19 Jak-STAT signaling Jak2 activation, structural basis 22, 23 Jak2 as molecular bridge 28, 29 overview 21, 22 Src family signaling interactions 25 27 STAT1 phosphorylation and nuclear localization 23 25 phospholipase C 19, 20, 51 Src kinases 20, 21, 25 27 structure 17 tubular transport modulation 49 51 AT2 developmental expression 103, 111 distribution in kidney 49, 161, 162 fibrosis role 83 functional effects of activation 18 knockout mouse phenotype 111 nuclear factor- B activation 129, 131 structure 18 transgenic mouse overexpression phenotype 78, 79 tubular transport modulation 50, 55, 59 Atherosclerosis angiotensin II role inhibitor effects 238, 239 experimental evidence 236 lipoprotein interactions 239 241 localization in arteries 235 reactive oxygen species induction 236 238 oxidative stress consequences 236, 237 renin-angiotensin system response 139 Autosomal dominant polycystic kidney disease, management 207 Blood pressure AT1 knockout mouse phenotypes 76 78 renoprotection therapy goals 208, 209 cdc2, cell cycle regulation 94, 95 Cell cycle angiotensin II-induced oxidative stress effects 238 cyclin-dependent kinase regulation 94 97 G 1 entry 95, 96 p21 regulation 96 p27 regulation 96, 97, 101, 102 phases 94 Collecting duct, angiotensin II effects on transport 57, 58 Creatinine, inhibitor effects 204 Cyclin-dependent kinase, cell cycle regulation 94 97 Diabetic nephropathy angiotensin II effects on renal cells 215, 216 signaling 216 inhibitor trials 194, 195 fibrosis angiotensin inhibition studies 178 inhibitor trials 180, 181 extracellular matrix synthesis and degradation 177, 178 glomerulosclerosis 176, 177 transgenic rat model 178, 179 protein kinase C activation 216, 217 renin-angiotensin system expression renal expression 213 215 systemic expression 212, 213 Distal tubule, angiotensin II effects on transport 56 58 Egr-1 angiotensin II induction of synthesis 143 Embryonic stem cell, transgenic mouse construction 73 End-stage renal disease progression 187 structural changes in kidney 92, 93 Subject Index 264
Fibrosis inhibitor attenuation 63 AT1 blockade effects 63, 82, 83, 156, 157 knockout mouse phenotype in model 83 AT2 role 83 diabetic nephropathy angiotensin inhibition studies 178 inhibitor trials 180, 181 extracellular matrix synthesis and degradation 177, 178 glomerulosclerosis 176, 177 transgenic rat model 178, 179 extracellular matrix changes degradation 176 glomerulosclerosis 172 overview 171, 172 tubulointerstitium 172, 173 growth factors and renin-angiotensin system 174 intervention studies 176 macrophage infiltration 175, 176 mechanical stress role 174, 175 plasminogen activator inhibitor-1 role 164, 165 resident cells and phenotypic changes 175 transforming growth factor- role angiotensin II induction of cytokine 155 inhibition studies 156, 157 expression levels 153, 154 inflammation mediation 157, 158 inhibition effects in animal models 154, 155 overview 153, 174 renin-angiotensin system response 155, 156 therapeutic targeting 158 unilateral ureteral obstruction 253 255 Fractalkine, angiotensin II induction of synthesis 128 Fyn, AT1 signaling role 26, 27, 29 Glomerular endothelial cell, angiotensin IIinduced proliferation 99, 100 Glomerular filtration rate angiotensin II blockade effects clinical renal disease 42 44 experimental renal insufficiency 39 endogenous angiotensin II effects 36 exogenous angiotensin II effects 34, 35 proteinuria correlation 193 Glomerular ultrafiltration coefficient angiotensin II blockade effects 41 exogenous angiotensin II effects 35 Glomerulosclerosis, see also Diabetic nephropathy, Fibrosis extracellular matrix changes 172 plasminogen activator inhibitor-1 role 165, 166 HMG-CoA reductase inhibitor, effects 145, 146 Hydronephrosis, angiotensin II effects 116 120, 256 Hyperkalemia, angiotension-converting enzyme inhibitor induction 205, 206 Inflammation, angiotension II mediation adhesion molecule upregulation 128 chemokine induction 125 128, 142 cytokine induction 129 diabetes 144 HMG-CoA reductase inhibitor effects 145, 146 inflammatory cell response 124, 147, 148 mitogen-activated protein kinase signaling 144, 146 nitric oxide mediation 143 nuclear factor- B pathway 130 132, 140 147 overview 123, 124 Ras signaling 146, 147 renal damage mediation 124 transgenic rat studies 144, 145 unilateral ureteral obstruction 252, 253 Interleukin-1, angiotensin II inductiion of synthesis 129 Subject Index 265
Interleukin-6, angiotensin II induction of synthesis 143 Jak-STAT signaling, AT1 Jak2 activation, structural basis 22, 23 Jak2 as molecular bridge 28, 29 overview 21, 22 Src family signaling interactions 25 27 STAT1 phosphorylation and nuclear localization 23 25 Kidney transplantation chronic allograft dysfunction angiotensin blockade effects 228 232 gene polymorphism 227 clinical features 222, 223 cyclosporine A nephrotoxicity 223, 224 cytokine mediation 225, 226 definition 222 histological features 223, 224 immune-dependent factors 224 juxtaglomerular apparatus hypertrophy 227 renin-angiotensin system activation 226, 227 transforming growth factor- role 225, 226, 228, 229 graft survival 222 renal artery stenosis 232 Knockout mouse, see specific genes Loop of Henle, angiotensin II effects cell proliferation 102 transport 55, 56, 58 Low-density lipoprotein angiotensin II interactions 239 241 apoptosis induction 240 oxidative stress induction 240 receptor induction by angiotensin II 241 Macula densa, angiotensin II effects on transport 56, 58 Mesangial cell, angiotensin II-induced hypertrophy 99, 215, 242, 243 Mitogen-activated protein kinase, angiotensin II inflammatory signaling 144, 146 Monocyte chemoattractant protein-1 angiotensin II induction of synthesis 126 128, 142 chronic allograft dysfunction role 230 Nephron, adaptation to injury 92, 93 Nitric oxide angiotensin II effects on production 216, 238 chronic allograft dysfunction role 229 inflammation mediation 143 Nuclear factor- B angiotension II inflammation pathway 130 132, 140 147 angiotensin III inflammation pathway 133, 142 angiotensinogen gene induction 141 Drosophila activation 139 promoter binding in inflammation 140 reactive oxygen species in activation 138, 139, 188 unilateral ureteral obstruction activation 252, 253 Obstructive nephropathy, see also Unilateral ureteral obstruction AT1 blockade effects adults 118, 119 knockout mouse phenotype 112 116 angiotensin II effects 116 120 Osteopontin, unilateral ureteral obstruction expression 253 Oxidative stress angiotensin II induction of reactive oxygen species 141, 236, 237, 242 atherosclerosis role 236, 237 hypertension role 138 low-density lipoprotein induction 240 renin-angiotensin system response 139 unilateral ureteral obstruction role 255 Phospholipase C, AT1 signaling role 19, 20, 51 Subject Index 266
Plasminogen activator inhibitor-1 aldosterone enhancement of angiotensin induction 163, 164, 168 angiotensin IV induction 67, 162, 163 chronic allograft dysfunction role 229 fibrosis role 164, 165 function 162 glomerulosclerosis role 165, 166 knockout mice 163 polymorphisms and expression regulation 162, 163 Platelet-derived growth factor, unilateral ureteral obstruction role 255 Protein kinase C, activation in diabetes 216, 217 Proteinuria angiotension II role 190, 191 inhibitor animal studies 194 chronic allograft dysfunction 231 clinical trials 192 195 diabetic nephropathy 194, 195 blood pressure, renoprotection therapy goals 208, 209 exogenous angiotensin II effects 35, 36 renal disease progression and protein traffic 187, 188, 190 Proximal tubule antiotensin II compartmentalization 6 8, 48 angiotensin II effects on transport inhibitory effects 53 55 stimulatory effects and signaling 50, 51, 53 angiotensin II-induced cell hypertrophy 100 102 RANTES angiotensin II induction of synthesis 127 chronic allograft dysfunction role 230 Ras, angiotensin II inflammatory signaling 146, 147 Reactive oxygen species, see Oxidative stress Renal allograft, see Kidney transplantation Renal blood flow angiotensin II blockade effects experimental renal insufficiency 39 endogenous angiotensin II effects 36 exogenous angiotensin II effects 34, 35 Renin diabetic expression 212 214 genes 72 kidney synthesis 1 knockout mouse phenotype 74, 76 transforming growth factor- effects on synthesis 155 unilateral ureteral obstruction expression 251 Rho, angiotensin II inflammatory signaling 146, 147 Sodium excretion angiotensin II blockade effects 37 AT1 knockout mouse phenotype 80, 81 Src kinases, AT1 signaling role 20, 21, 25 27 STAT, see Jak-STAT signaling Transforming growth factor- angiotensin II mediation in diabetes 215, 217 chronic allograft dysfunction role 225, 226, 228, 229 fibrosis role angiotensin II induction of cytokine 155 inhibition studies 156, 157 expression levels 153, 154 inflammation mediation 157, 158 inhibition effects in animal models 154, 155 overview 153 renin-angiotensin system response 155, 156 therapeutic targeting 158 unilateral ureteral obstruction role 253, 254 Transgenic mouse, see specific genes Tubuloglomerular feedback AT1 knockout mouse phenotype 79, 80 angiotensin II role 38, 56 Subject Index 267
Tumor necrosis factor- angiotensin II induction of synthesis 129, 142 unilateral ureteral obstruction expression 253 Unilateral ureteral obstruction inhibitor effects 250 253 congenital urinary tract obstruction 255, 256 guinea pig model 250 hemodynamics 250, 251 interstitial fibrosis 253 255 interstitial inflammation 252, 253 oxidative stress role 255 rat model 251 renin expression 251 tubular atrophy and apoptosis 252 Vascular endothelial growth factor, chronic allograft dysfunction role 230 Water homeostasis, AT1 knockout mouse phenotype 81, 82 Subject Index 268