Liver Angiotensinogen Is the Primary Source of Renal Angiotensin II

Abstract

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

Renal Angiotensin-Converting Enzyme Is Essential for the Hypertension Induced by Nitric Oxide Synthesis Inhibition

“…9,22 Although most investigators agree that overexpression of RAS components along the nephron results in hypertension, [23][24][25][26] the question becomes whether the local RAS works as a separate entity or whether it represents an extension of the systemic RAS. 9,27 Our data argue in favor of the former hypothesis. L-NAME was purposely chosen because it suppresses plasma renin activity, 10,11 minimizing potential contributions of the systemic RAS.…”

Multiphoton Imaging of the Glomerular Permeability of Angiotensinogen

“…A recently published work by Matsusaka et al 33 using kidney-or liver-specific and dual AGT null mice provided additional support that, in the normal kidney, only a minor but detectable fraction of plasma AGT is filtered. However, disruption of the GFB led to the leakage of massive amounts of AGT protein into the tubular lumen, which was then reabsorbed by proximal tubular cells.…”

The Increasing Complexity of the Intratubular Renin-Angiotensin System

“…18 The important question of the quantitative contribution of either source to total renal AGT content remained unresolved because of the lack of definitive tools needed to provide the answer. The paper by Matsusaka et al 20 in this issue of JASN provides critical data obtained in mice that had either liver AGT or the kidney AGT mRNA expression deleted genetically. Their results show that kidney-specific AGT-null mice have kidney AGT protein and AII levels similar to those in control mice, whereas the liver-specific AGT-null mice have markedly lower or undetectable levels of AGT in the proximal tubules and kidney AII.…”