Lara LS, McCormack M, Semprum-Prieto LC, Shenouda S, Majid DS, Kobori H, Navar LG, Prieto MC. AT1 receptormediated augmentation of angiotensinogen, oxidative stress, and inflammation in ANG II-salt hypertension. Am J Physiol Renal Physiol 302: F85-F94, 2012. First published September 7, 2011 doi:10.1152/ajprenal.00351.2011.-Augmentation of intrarenal angiotensinogen (AGT) synthesis, secretion, and excretion is associated with the development of hypertension, renal oxidative stress, and tissue injury during ANG II-dependent hypertension. High salt (HS) exacerbates hypertension and kidney injury, but the mechanisms remain unclear. In this study, we determined the consequences of HS intake alone compared with chronic ANG II infusion and combined HS plus ANG II on the stimulation of urinary AGT (uAGT), renal oxidative stress, and renal injury markers. Sprague-Dawley rats were subjected to 1) a normal-salt diet [NS, n ϭ 5]; 2) HS diet [8% NaCl, n ϭ 5]; 3) ANG II infusion in NS rats [ANG II 80 ng/min, n ϭ 5]; 4) ANG II infusion in HS rats [ANG IIϩHS, n ϭ 5]; and 5) ANG II infusion in HS rats treated with ANG II type 1 receptor blocker (ARB) [ANG IIϩHSϩARB, n ϭ 5] for 14 days. Rats fed a HS diet alone did not show changes in systolic blood pressure (SBP), proteinuria, cell proliferation, or uAGT excretion although they did exhibit mesangial expansion, collagen deposition, and had increased NADPH oxidase activity accompanied by increased peroxynitrite formation in the kidneys. Compared with ANG II rats, the combination of ANG II infusion and a HS diet led to exacerbation in SBP (175 Ϯ 10 vs. 221 Ϯ 8 mmHg; P Ͻ 0.05), proteinuria (46 Ϯ 7 vs. 127 Ϯ 7 mg/day; P Ͻ 0.05), and uAGT (1,109 Ϯ 70 vs.. 7,200 Ϯ 614 ng/day; P Ͻ 0.05) associated with greater collagen deposition, mesangial expansion, interstitial cell proliferation, and macrophage infiltration. In both ANG II groups, the O 2 Ϫ levels were increased due to increased NADPH oxidase activity without concomitant increases in peroxynitrite formation. The responses in ANG II rats were prevented or ameliorated by ARB treatment. The results indicate that HS independently stimulates ROS formation, which may synergize with the effect of ANG II to limit peroxynitrite formation, leading to exacerbation of uAGT and greater injury during ANG II salt hypertension. renin-angiotensin system; reactive oxygen species; kidney injury; macrophage infiltration; dihydroethidium staining THE ENHANCEMENT OF INTRARENAL angiotensin II (ANG II) content contributing to hypertension and kidney damage is supported by the presence of all components of the renin-angiotensin system (RAS) in the kidney (27-29). During ANG II-dependent hypertension, intrarenal RAS activation is characterized by increased tissue levels of ANG II due to an augmented ANG II type 1 receptor (AT 1 R) binding with concomitant internalization of circulating ANG II (5, 40) and by de novo formation of ANG II (30). In response to chronic ANG II infusions, there are 1) enhancement of angiotensinogen (AGT) synthesis and secretion by...