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. 2006 May;19(5):541-50.
doi: 10.1016/j.amjhyper.2005.11.014.

Young Scholars Award Lecture: Intratubular angiotensinogen in hypertension and kidney diseases

Hiroyuki Kobori  1 , Yuri Ozawa, Yuki Suzaki, Minolfa C Prieto-Carrasquero, Akira Nishiyama, Tatsuya Shoji, Eric P Cohen, L Gabriel Navar
Affiliations

Young Scholars Award Lecture: Intratubular angiotensinogen in hypertension and kidney diseases

Hiroyuki Kobori et al. Am J Hypertens. 2006 May.

Abstract

Recent findings related to the renin-angiotensin system have provided a more elaborated understanding of the pathophysiology of hypertension and kidney diseases. These findings have led to unique concepts and issues regarding the intrarenal renin-angiotensin system. Angiotensinogen is the only known substrate for renin that is the rate-limiting enzyme of the renin-angiotensin system. Because the level of angiotensinogen in human beings is close to the Michaelis-Menten constant value for renin, changes in angiotensinogen levels can control the activity of the renin-angiotensin system, and its upregulation may lead to elevated angiotensin peptide levels and increases in blood pressure. Enhanced intrarenal angiotensinogen mRNA or protein levels or both have been observed in multiple models of hypertension including angiotensin II-dependent hypertensive rats, Dahl salt-sensitive hypertensive rats, and spontaneously hypertensive rats, as well as in kidney diseases including diabetic nephropathy, immunoglobulin A (IgA) nephropathy, and radiation nephropathy. Renal angiotensinogen is formed primarily in proximal tubular cells and is secreted into the tubular fluid. Urinary angiotensinogen excretion rates show a clear relationship to kidney angiotensin II contents and kidney angiotensinogen levels, suggesting that urinary angiotensinogen may serve as an index of the intrarenal renin-angiotensin system status. Establishment of concise and accurate methods to measure human angiotensinogen may allow clinical studies that would provide important information regarding the roles of intrarenal angiotensinogen in the development and progression of hypertension and kidney diseases.

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Figures

FIG. 1
FIG. 1
Kidney angiotensinogen immunostaining showed a significant enhancement in angiotensin II-infused rats (center panel) compared with sham-operated rats (left panel). Use of AT1 receptor blockade (ARB) prevented this augmentation (right panel). Kidney angiotensinogen immunohistochemistry was performed as previously described using an automatic robotic system (Dako autostainer) to apply the exactly same condition on all slides.
FIG. 2
FIG. 2
Kidney angiotensinogen protein levels were significantly increased in Dahl salt-sensitive rats (DS) on a high-salt diet (HS) compared with DS on a low-salt diet (LS). Tempol (T) but not hydralazine (H) treatment prevented the intrarenal angiotensinogen augmentation.
FIG. 3
FIG. 3
Kidney angiotensinogen mRNA levels were not changed in Wistar-Kyoto rats (WKY) at 7 weeks of age or WKY at 14 weeks of age. However angiotensinogen mRNA levels were significantly increased in spontaneously hypertensive rats (SHR) at 14 weeks of age compared with SHR at 7 weeks of age and the age-matched WKY. Treatment with AT1 receptor blockers (ARB) prevented the augmentation of angiotensinogen mRNA. However, a triple therapy of hydralazine, reserpine, and hydrochlorothiazide (HRH) failed to prevent this augmentation.
FIG. 4
FIG. 4
Enhanced intrarenal angiotensinogen immunoreactivity in immunoglobulin-A (IgA) nephropathy patients. Immunohistochemistry robotic system was used to apply a specimen in the exact same condition on each slide. Immunoreactivity of human angiotensinogen was significantly increased in kidneys of IgA nephropathy patients (right panel) compared with kidneys of normal subjects (left panel).
FIG. 5
FIG. 5
Enhanced intrarenal angiotensinogen protein levels in experimental radiation nephropathy in rats. Western blot analysis indicates that angiotensinogen protein levels significantly increased in a time-dependent manner after total body irradiation.
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