경희대학교 의과대학 내과학교실 문 주 영 Renin-angiotensin-aldosterone system (RAAS) : Old and New

Contents Physiologic and pathologic role of RAAS RAAS Blocker New components of RAAS

Renin-Angiotensin-Aldosterone System(RAAS) : systemic effect of Ang II

Pathophysiological effects of Angiotensin II Diabetes Care 2009;32(Suppl 2):S410-S413

Angiotensin II Plays a Central Role in Organ Damage A II AT 1 receptor GFR Proteinuria Aldosterone release Glomerular sclerosis Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction LV hypertrophy Fibrosis Remodeling Apoptosis Stroke DEATH Hypertension Heart failure MI Renal failure

Series of disease …

Francois Cambien et al, Nature 359, 1992 ACE Polymorphism

Ju-Young Moon et al, Nephron Clin Pract;111: , 2009

Blood pressure – Any effect of the D allele on hypertension must be very small. Atherosclerosis – There is a possible interaction between carotid IMT Coronary heart disease – D allele is not clinically important in the general population, but may play an important role in certain groups of patients. Diabetic nephropathy – There is solid evidence between ACE gene and diabetic nephropathy. F.A. Sayed-Tabatabaei et al, Circulation Research 98: , 2006 ACE Polymorphism and clinical outcomes

The kidney contains all the elements of the RAAS, and intrarenal formation of Ang II independent of the circulating RAAS. Elements of intrarenal RAAS – Angiotensinogen : Proximal tubular cell – Renin : Juxtaglomerular cell, connecting tubule, collecting duct – (Pro)renin receptor : Mesangial cell, podocyte – Angiotensin-converting enzyme : Proximal to collecting cell, endothelial cell – Ang II receptor (AT1R) : Vascular, glomerular, tubular – Aldosterone : Podocyte (rat data) Intrarenal RAAS

Systemic RASIntrarenal RAS Intrearenal Ang II : 3-5 nmol/L Hiroyuki Kobori et al, Phamacological Reviews 59: , 배 !

Intrarenal RAAS 의 특이점 Unlike juxtaglomerular cells where Ang II inhibits renin release via the AT 1 receptor, in the collecting duct Ang II stimulates renin expression via the AT 1 receptor. The enhanced intrarenal angiotensinogen mRNA levels and angiotensinogen secretion depend on AT1 receptor activation.

Augmentation of the intrarenal RAAS during progression of renal injury :The paradox of low renin state in diabetic nephropathy Deborah A. Price et al, J Am Soc Nephrol 10: , 1999

The renal blood flow: Autoregulation Change in the delivery of NaCl to the macula densa region of the TAL causes changes in afferent arteriolar caliber. The response mediated by adenosine and/or ATP and modulated by other locally produced agents such as angiotensin II and nitric oxide. Increased macula densa NaCl delivery results in afferent arteriolar constriction, thereby reducing GFR

Angiotensin II receptor blockade reduces intrarenal vascular resistance in patients with Type 2 DM Danilo Fliser et al. J Am Soc Nephrol 16: , 2005

Ruggenenti, P et al. Nat Rev Nephrol 2010; 6: RAAS Blocker

ACE inhibitor, angiotensin II receptor blocker 처방 후 F/U 해야 하는 검사 두 가지를 쓰시오. 1) 2) 2011 내과 전문의 시험 주관식 출제

혈압 조절 심부전 환자의 생존율 증가 단백뇨의 감소 만성 신부전 환자의 신기능 감소 억제 LC 환자에서의 복수 조절 Stroke 환자의 예방 치프샘이 쓰라고 하니까 … Indications of RAAS Blocker

혈압 조절에서의 RAAS blocker 의 적응증

최근 RAAS blocker 의 대규모 임상 연구

N Eng J Med ;364:907-17, 2011

RAAS 을 전부 차단할 수 있을까 ?

New components of RAAS

Binding of renin/prorenin to the (pro)renin receptor

Angiotensin 1-9 Angiotensin 1-7 Angiotensinogen Angiotensin I Angiotensin II Angiotensin receptor AT1, AT2 Renin ACE Aldosterone Mas receptor ACE2 Renin-angiotensin-aldosterone system

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-R Angiotensinogen Angiotensin I Angiotensin II Angiotensin III Angiotensin IV Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu Asp-Arg-Val-Tyr-Ile-His-Pro-Phe Arg-Val-Tyr-Ile-His-Pro-Phe Val-Tyr-Ile-His-Pro-Phe Renin cleavage site ACE cleavage site Phospholipase A cleavage site Aminopeptidase B cleavage site RAS components & site of enzyme cleavage

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu Asp-Arg-Val-Tyr-Ile-His-Pro-PheAsp-Arg-Val-Tyr-Ile-His-Pro-Phe-His Asp-Arg-Val-Tyr-Ile-His-Pro Ang I Ang II Ang1-9 Ang1-7 ACEACE2 ACE ACE2 ACE and ACE

Vasodilation Endothelial function Proliferation Hypertrophy Fibrosis Thrombosis Antiarrhythmogenic Vasoconstriction Endothelial dysfunction Proliferation/hypertrophy Fibrosis Atherosclerosis Arrhythmogenesis Thrombosis Angiotensin II Angiotensin 1-7 AT1 receptorMas

ACE2 KO mice Wild-type mice Gurley et al, J Clin Invest;116, 2006

Wysocki J et al, Hypertension;55,2010

Ju-Young Moon et al, Am J Physiol Renal Physiol: 300, 2011

Tikellis et al, Diabetes: 57,2008

Michiya igase et al, Am J Physiol Heart Circ Physiol;289, 2005 ControlACE2

Renin-angiotensin-aldosterone system 은 심혈관계와 신장 질환에 있어 여전히 중요한 조절 인자이다. 특히, 신장은 모든 RAAS 을 가지고 있으며, 신장 질환의 경우 systemic circulation 과 독립적으로 작용하기도 한다. 기존의 ACE-Ang II-AT1 receptor axis 와 달리, ACE2-Ang-(1-7)-Mas receptor axis 의 경우, 새로운 각도에서 연구가 필요하다.