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Tissue renin angiotensin system


  • 1. Newer Concepts in RAAS:Tissue, and Cardiac RAAS Dr Amarpal Singh GulatiAsst. Prof. Dept. of Cardiology Nizams Institute of medical Sciences

2. DenitionThe renin-angiotensin system (RAS) is apeptidergic system with endocrinecharacteristics. 3. How the RAAS Was Seen in the PastSubstrate : Angiotensinogen, an -glycoprotein,released from the liverIn the circulation, enzyme renin, secreted from theII main effector Circulating Angjuxtaglomerular apparatus of the kidney forms thedecapeptide angiotensin (ANG) I. Involved inglobal regulation of sympatheticANG I is then activated to the octapeptide ANG II byangiotensin converting enzyme (ACE), a activity Regulation of blood pressuremembrane-bound metalloproteinase, which is Fluid and electrolyte balancepredominantly expressed in high concentrations onthe surface of endothelial cells in the pulmonarycirculation.ANG II, considered the main effector peptide of theRAS, which acts on specic receptors on vascularsmooth muscle cells to induce vasoconstriction or,by stimulating the release of aldosterone from theadrenal cortex. Vascular Disease Prevention, 2009, 6, 65-74 4. POSITIVE FEEDBACK EXISTS BETWEEN DISEASE PROCESSES IN THE CARDIORENAL CONTINUUMHTNRAAS activity Ang II Oxidative stress/ VasoconstrictionIGTDM riskCVD riskGFRSCr Glomerular pressureAtherosclerosiscardiac hypertrophyfibrosis,GlomerularsclerosisMAUUAER nephropathy of diabetic and nondiabetic etiology. Macro-CKD albuminuria proteinuria Predicts stroke,Technical Advances ESRD CHD, CVD risk 1. molecular biologyCHD=coronary heart disease; IGT=impaired glucose tolerance; UAER=urinary albumin excretion rate rat2. Availability of transgenic and knock-outmodelsCHD=coronary heart disease; IGT=impaired glucose tolerance; UAER=urinary albumin excretion ratewith altered expression of RAS components.Kopyt NP. JAOA. 2005;105:20715.4Kopyt NP. JAOA. 2005;105:20715. 5. Circulating Ang II levels tend to increase inpatients taking ACE inhibitors over longperiods. ACE is not the only enzyme implicated in thegeneration of Ang II 6. Interplay of recently discovered components of the renin angiotensin aldosterone system.Alternative pathways of ANG II formationConcept of local or tissue reninangiotensin systems Additional truncated peptides(1-9) & (1-7) Different ANG receptors andsignal transduction pathwaysEuropean Heart Journal (2011) 32, 27392747 7. Prorenin can be activated by Proteolytic :Endopeptidases/trypsin/cathepsin B or Nonproteolytic :low pH Three receptorsMannose-6-phosphate receptor (M6P) Endothelial cells Clearance mechanism Prorenin binding proteinCardiac cellsLocal tissue RAAS 45-kDa membrane protein binding both prorenin and renin Angiotensin independent effects Cofactor in increase production of Ang I Activation of promyelocytic zinc nger (PLZF) protein-phosphatidylinositol-3-kinase mitogen-activated protein kinases (MAPKs) localized in the mesangium (kidney) and in the subendothelium of renal, uterine, and cardiac blood vessels 8. Newer Theraupeutic Targets1Direct renin inhibitors DRIslike aliskirenattenuate the plasma renin activity which isincreased by ACE inhibition or AT1R blockadeHigh renin levels cause escape from renin inhibitionDo not prevent binding of renin to the (P)RR. A handling region peptide (HRP) inhibiting the binding of prorenin to (P)RR,completely abolished diabetic nephropathy in AT1R knockout mice2 Reduced cardiac brosis in stroke-prone SpontaneouslyAngiotensinHypertensive RatsIndependent reduced cardiac hypertrophy and brosis EffectsHRP were only effective in low-renin conditionsIchihara A et al. Hypert ens Res 2010;33:177 180Susic D et al. Am J Physiol Heart Circ Physiol 2008;295:H1117 H1121. 9. cleavage of the COOH-terminal dipeptideAngiotensin converting enzyme ACE independent enzyme activity chymases, In circulation high substrate specicity Cellular localization largely restricted to mast cells Normally remains inactivated Locally expressed Selective chymase inhibitors used in animal models Mediate > 80% of AngII formation in carboxypeptidases,the heart and >60% in the vessels cathepsin G Not inhibited by ACE inhibitors tonin.Upregulation during pathologic conditions causing increased local Ang neprylisin II generation Also form Alternative cleavageproducts 10. White bars : nondiabetic controls(control)Black bars : streptozotocin (STZ)-induced diabetic hamsters (STZ)Hatched bars : STZ hamsters renderednormoglycemic by continuousintraperitoneal insulin infusion (STZ CIPII).Quantication of hamster chymase and ACE mRNA in the kidney by real-time PCR.Results are shown as a percentage of controls. 11. ACE (dipeptidyl-carboxypeptidase) subtypes Two distinct forms of ACE Two active sites Somatic form on the endothelial N-terminal domain cells(lung, smooth muscle cells, Ang 1-7 cleavage monocytes, T lymphocytes, and C-terminal domain adipocytes) Responsible for Ang I conversion Germinal form (testis) Selective C domain inhibition is glycosylphosphatidylinositol (GPI)sufficient to prevent Ang Iinducedhydrolase activity not inhibited by ACE vasoconstrictioninhibitors Both sites required for degradation of capacitation, formation of the spermbradykininmembrane,located on the 1. endothelium of all blood vessels Two types of Existence 2. In the parenchyma of the At the cell surface (ectoenzymes) heart, kidneys, brain, and adrenal hydrolyzing circulating peptidesglands. 2. Also in non- Soluble form (plasma ACE) after actionendothelial cells such as of ACE secretasemacrophage lungs have traditionally beenconsidered to be an integral part of thecirculating RAS 10% of total ACE Risk factor for coronary stent restenosis,CAD, MI and post MI LV dilationAnchored to the plasmamembrane 12. Local or tissue renin angiotensin systems RAS components in unlikely places such as the kidney enzyme renin in the brain Local expression of angiotensinogen, renin, renin-binding protein, ACE,chymase, as well as Ang II receptors and secretion of Ang II. Tissue-based synthesis of ANG II Angiotensin and renin messenger RNA (mRNA) has been discovered in12 different extrahepatic tissues of rats, strongly suggesting that thereis local synthesis of angiotensinogen and renin Local synthesis or Uptake from the circulation Clinical relevance : Dissociating from the class effect 13. Both Local and systemic actions of the RAS integrate and cause ANG-mediated effects Though An independent function of local RAS (for example, in the brain, inside theblood-brain barrier as well as in testis/ovary/bonemarrow and so on) Local RAAS at the cellular level Paracrine Autocrine effects cell growth, proliferation, and metabolism Intracellular or intracrine RAS sffects ANG binding in the cell nucleus 14. The renin-angiotensin system (RAS) in the heart.ContractilityChronotropyHypertrophyApoptosisFibrosisInducers of ACE1. Vol or press overload2. Wall stress3. CHF4. MI5. agingendothelium Physiol Rev VOL 86 JULY 2006 15. Van Kats et al. used infusions of radiolabeled ANG I and ANG II peptides in pigs andmeasured plasma and tissue levels of endogenous as well as the radiolabeledpeptides.>90% of cardiac ANG I is synthesized locally in the heart>75% of cardiac ANG II is synthesized locally, most of it using local ANG I generationas a basis.Concept of a cardiacClinically,dependent only on the extremely of 1) RAS is not ACE inhibitors are local synthesisangiotensinogen and renin. in the treatment of cardiac disease; efcientACE independent pathwaysTissue ACE is regarded as the vital rate limiting enzyme in the local elaboration ofAII 2) Most of the ANG II generatedin intact cardiacare particularly importantbydisease states such as cardiac blood vessels can heartblocked by ACE hypertrophy and be failure inhibitors;. Even partial inhibition of cardiac ACE has been shown to contribute to thee.g,benecial effects associatedACE expression is higher in with ACE inhibitors in patients with heart failure,hypertension, or coronary artery disease as well as inruptured plaque 3) Expression of human heart chymase is highlythe macrophages aroundcompartmentalized and mostly restricted to ruptured plaquemast cells 16. Activation of a local renin-angiotensin system (RAS) in heartIPC~50,000 mast cells/g humanheart tissue in close proximityto vessels and nerves Density further increases inheart failure, ischemiccardiomyopathy andexperimental infarct modelsCirculation. 2010 August 24; 122(8): 771781 17. RAS after LVADEuropean Heart Journal (2009) 30, 805812 18. Local RASS in Kidney Proximal tubular cell 1. Unlike heart Ang II is requiredfor normal renal development 2. Activated by Hyperglycemia Proteinuria Renal injury Reduction in calcitriol 3. ACEIs do not significantlyreduce intrarenal AngIIproduction which is regionally4. Never the less, antihypertensive therapy withcompart-mentalized and inACE inhibitors, successfully ameliorates proteinuriaendosomessuggesting benecial effects independent ofreductions in blood pressure.5. Also decreases risk associated with death,dialysis, increased creatinine, and transplantationWolf G et al. Nephron Physiol 93: 313, 2003 19. Tissue ACE and the Vasculature Endothelial cells cover 700 m2 and weigh 1 Locally produced AII is responsible forto 1.5 kg in a 70-kg individualendothelial dysfunction. Vascular homeostasis Local renin production as well as relaxation and contraction; endothelial ACE upregulation occurs in thrombogenesis and brinolysis; response to injury platelet activation and inhibition; Hypercholesterolemia, Cellular growth stimulation and inhibition. smoking, hypertension, The vascular wall is the effector organ for the aging,hormonal or plasma RAS Diabetes The substrate mRNA levels are abundantly Expression of ACE is further modulatedexpressed in periadventitial fat cells by steroids, calcium ionophores, Renin uptake also takes place via unspecied growth factorsbinding sites on endothelial cells or specicprorenin/renin recept