Angiotensin II content in the kidney is much higher than in the plasma, and it increases more in kidney diseases through an uncertain mechanism. Because the kidney abundantly expresses angiotensinogen mRNA, transcriptional dysregulation of angiotensinogen within the kidney is one potential cause of increased renal angiotensin II in the setting of disease. Here, we observed that kidney-specific angiotensinogen knockout mice had levels of renal angiotensinogen protein and angiotensin II that were similar to those levels of control mice. In contrast, liver-specific knockout of angiotensinogen nearly abolished plasma and renal angiotensinogen protein and renal tissue angiotensin II. Immunohistochemical analysis in mosaic proximal tubules of megalin knockout mice revealed that angiotensinogen protein was incorporated selectively in megalin-intact cells of the proximal tubule, indicating that the proximal tubule reabsorbs filtered angiotensinogen through megalin. Disruption of the filtration barrier in a transgenic mouse model of podocyte-selective injury increased renal angiotensin II content and markedly increased both tubular and urinary angiotensinogen protein without an increase in renal renin activity, supporting the dependency of renal angiotensin II generation on filtered angiotensinogen. Taken together, these data suggest that liverderived angiotensinogen is the primary source of renal angiotensinogen protein and angiotensin II. Furthermore, an abnormal increase in the permeability of the glomerular capillary wall to angiotensinogen, which characterizes proteinuric kidney diseases, enhances the synthesis of renal angiotensin II. CKDs are often progressive and involve cardiovascular diseases. Pharmacological intervention of angiotensin II (AII) is the only currently available therapeutic clinical measure with proven effectiveness in protecting the kidney from progressive loss of renal function in CKD. However, in these conditions, circulating AII is typically not elevated. Of note, AII content in renal tissues is markedly higher than content in the circulation, and it is regulated in a manner distinct from circulating AII. 1-3 These findings have formed the currently prevailing notion that the kidney in and of itself is furnished with a full set of components necessary for de novo AII synthesis. In support of this notion, studies have shown that renal AII is elevated in hypertension and
The serum level of pepsinogen I (PG I) and pepsinogen II (PG II), and the PG I/PG II ratio were compared with the surface area of the fundic mucosa, as determined endoscopically by the Congo red staining method. Reduction in the area of the fundic mucosa due to gastritis was associated with stepwise reduction in the PG I levels and the PG I/PG II ratios. Reduction in the area of the fundic mucosa was also associated with decreases in the basal acid output, maximal acid output (MAO), the basal pepsin output and the stimulated pepsin output. The best sensitivity and specificity levels for the diagnosis of normal mucosa and severe gastritis were obtained with the PG I/PG II ratio and the MAO. A retrospective study of 58 patients with gastric cancer and 162 cancer-free patients showed that a PG I/PG II ratio identified 86.2% of all carcinomas and 87.5% of early carcinomas. Although this test gave a positive rate of 36% among the cancer-susceptible age group controls, its use would lower the cost of mass screening by targeting a smaller test population.
Abstract-In the present study, we tested the hypothesis that the renoprotective effect of an angiotensin receptor blocker depends on the angiotensin II type 1 (AT 1 ) receptor on podocytes. For this purpose, we generated podocyte-specific knockout mice for the AT 1 gene (Agtr1a) and crossed with NEP25, in which selective podocyte injury can be induced by immunotoxin, anti-Tac(Fv)-PE38. Four weeks after the addition of anti-Tac(Fv)-PE38, urinary albumin:creatinine ratio was not attenuated in Agtr1a knockout/NEP25 mice (nϭ18) compared with that in control NEP25 mice (nϭ13; 8.08Ϯ2.41 in knockout versus 4.84Ϯ0.73 in control). Both strains of mice showed similar degrees of sclerosis (0.66Ϯ0.17 versus 0.82Ϯ0.27 on a 0 to 4 scale) and downregulation of nephrin (5.78Ϯ0.45 versus 5.65Ϯ0.58 on a 0 to 8 scale). In contrast, AT 1 antagonist or an angiotensin I-converting enzyme inhibitor, but not hydralazine, remarkably attenuated proteinuria and sclerosis in NEP25 mice. Moreover, continuous angiotensin II infusion induced microalbuminuria similarly in both Agtr1a knockout and wild-type mice. Thus, angiotensin inhibition can protect podocytes and prevent the development of glomerulosclerosis independent of podocyte AT 1 . Possible mechanisms include inhibitory effects on AT 1 of other cells or through mechanisms independent of AT 1 . Our study further demonstrates that measures that directly affect only nonpodocyte cells can have beneficial effects even when sclerosis is triggered by podocyte-specific injury. (Hypertension. 2010;55:967-973.)Key Words: podocyte Ⅲ glomerulosclerosis Ⅲ chronic renal failure Ⅲ AT 1 antagonist Ⅲ knockout mice Ⅲ proteinuria P odocytes play an indispensable role as a filtration barrier for macromolecules in the glomerulus. Damage of podocytes is a key step triggering the progression of glomerulosclerosis. A large volume of evidence indicates that angiotensin (Ang) II acting on the Ang II type 1 receptor (AT 1 ) plays important roles in this process. Blockade of Ang II synthesis with Ang I-converting enzyme (ACE) inhibitors or of Ang II action with AT 1 receptor blocker (ARB) is a clinically established therapeutic measure for slowing the progression of chronic kidney diseases. ACE inhibitors and ARBs have been shown to attenuate podocyte damage, proteinuria, and development of glomerulosclerosis in a variety of animal models, including, among others, 1-7 the subtotal nephrectomy model 8 and diabetic nephropathy models. 9,10 Continuous infusion of Ang II in normal rats increased desmin expression 11 and suppressed nephrin and podocin mRNA. 6 Studies conducted thus far collectively indicate that Ang II is involved in triggering, enhancing, and expanding podocyte injury and in the progression of glomerular injury toward sclerosis through mechanisms beyond its effect on systemic blood pressure.Because podocyte injury along with proteinuria ubiquitously precedes progressive development of glomerulosclerosis, and because Ang II inhibition attenuates podocyte damage and progressive glomerulosclerosis, it...
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