The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease.
In recent years, the focus of interest on the role of the renin-angiotensin system (RAS) in the pathophysiology of hypertension and organ injury has changed to a major emphasis on the role of the local RAS in specific tissues. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by independent multiple mechanisms. Proximal tubular angiotensinogen, collecting duct renin, and tubular angiotensin II type 1 (AT1) receptors are positively augmented by intrarenal Ang II. In addition to the classic RAS pathways, prorenin receptors and chymase are also involved in local Ang II formation in the kidney. Moreover, circulating Ang II is actively internalized into proximal tubular cells by AT1 receptor-dependent mechanisms. Consequently, Ang II is compartmentalized in the renal interstitial fluid and the proximal tubular compartments with much higher concentrations than those existing in the circulation. Recent evidence has also revealed that inappropriate activation of the intrarenal RAS is an important contributor to the pathogenesis of hypertension and renal injury. Thus, it is necessary to understand the mechanisms responsible for independent regulation of the intrarenal RAS. In this review, we will briefly summarize our current understanding of independent regulation of the intrarenal RAS and discuss how inappropriate activation of this system contributes to the development and maintenance of hypertension and renal injury. We will also discuss the impact of antihypertensive agents in preventing the progressive increases in the intrarenal RAS during the development of hypertension and renal injury.
Kobori
Hiroyuki
H
Department of Medicine, Director of the Molecular Core in Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, LA 70112-2699, USA. hkobori@tulane.edu
Nangaku
Masaomi
M
Navar
L Gabriel
LG
Nishiyama
Akira
A
D000804:Angiotensin II / Q000502:physiology; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D002908:Chronic Disease; D004195:Disease Models, Animal; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D006977:Hypertension, Renal / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply / Q000378:metabolism / Q000502:physiology*; D007674:Kidney Diseases / Q000503:physiopathology*; D011945:Receptors, Angiotensin / Q000502:physiology; D012083:Renin / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology*
D000959:Antihypertensive Agents; D011945:Receptors, Angiotensin; D000808:Angiotensinogen; D000804:Angiotensin II; D012083:Renin