Kidney-specific enhancement of ANG II stimulates endogenous intrarenal angiotensinogen in gene-targeted mice

Kidney-specific enhancement of ANG II stimulates endogenous intrarenal angiotensinogen in gene-targeted mice. Am J Physiol Renal Physiol 293: F938-F945, 2007. First published July 18, 2007; doi:10.1152/ajprenal.00146.2007.- This study was performed in transgenic mice to test the hypothesis that the selective intrarenal overproduction of ANG II increases intrarenal mouse ( m) angiotensinogen (AGT) expression. We used the following three groups: 1) single transgenic mice ( group A, n = 14) expressing human ( h) AGT only in the kidney, 2) double-transgenic mice ( group D, n = 13) expressing human renin systemically in addition to hAGT only in the kidney, and 3) wild-type ( group W, n = 12) mice. Exogenous hAGT protein is inactive in group A because endogenous mouse renin cannot cleave hAGT to ANG I because of a high species specificity. All mice were monitored from 12 to 18 wk of age. Systolic blood pressure progressively increased from 116 +/- 5 mmHg ( 12 wk) to 140 +/- 7 ( 18 wk) in group D. This increase was not observed in groups A or W. Intrarenal hAGT levels were similar in groups A and D; however, hAGT was not detectable in kidneys of group W. Kidney ANG II levels were increased in group D ( 216 +/- 43 fmol/g) compared with groups A ( 117 +/- 16) and W ( 118 +/- 17). However, plasma ANG II concentrations were similar among the three groups. Endogenous renal mAGT mRNA was increased significantly in group D ( 1.46 +/- 0.19, ratio) compared with groups A ( 0.97 +/- 0.12) and W ( 1.00 +/- 0.08). Endogenous renal mAGT protein was also significantly increased in group D compared with groups A and W. Interstitial collagen-positive area, interstitial macrophage/monocyte infiltration, and afferent arteriolar wall thickness were increased significantly in group D compared with groups A and W. These data indicate for the first time that the selective stimulation of intrarenal production of ANG II from hAGT augments endogenous intrarenal mAGT mRNA and protein expression.