Augmentation of kidney angiotensinogen expression and urinary angiotensinogen excretion by an intracellular angiotensin II fusion protein (1173.8)

Abstract

Long‐term angiotensin II (ANG II) administration significantly increases ANG II levels in the kidney through two major mechanisms; AT1 receptor‐mediated augmentation of angiotensinogen (AGT) expression and uptake of circulating ANG II by the proximal tubule. However, it is not known if intracellular ANG II also stimulates AGT expression and secretion in the proximal tubule of the kidney. In the present study, we performed intrarenal adenoviral transfer of an intracellular cyan fluorescent fusion of ANG II (Ad‐sglt2‐ECFFP/ANG II) selectively in the proximal tubule using the sodium and glucose co‐transporter 2 (sglt2) promoter. AGT mRNA expression in the renal cortex and 24 h urinary AGT excretion were determined 2 and 4 weeks after ECFP/ANG II transfer. ECFP/ANG II was expressed in the proximal tubule in a time‐dependent manner, which was associated with significant increases in blood pressure 4 weeks after ECFP/ANG II transfer (p<0.01). AGT mRNA expression in the cortex was significantly increased at Week 4 by 61 ± 16% (p<0.05). Urinary AGT excretion rates were increased from 48.7 ± 5.7 (n=13) to 102 ± 13.5 (n=13) ng/24 h (p<0.05). However, plasma AGT levels were not altered. These results support the hypothesis that intracellular ANG II stimulates AGT expression in the proximal tubule leading to increased AGT formation and secretion into the tubular fluid.Grant Funding Source: Supported by P30GM10337 and RO1DK067299