title: Augmentation of angiotensinogen expression in the proximal tubule by intracellular angiotensin II via AT1a/MAPK/NF-кB signaling pathways.
abstract: Long-term angiotensin II (ANG II) infusion 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 tubules. However, it is not known whether intracellular ANG II stimulates AGT expression in the proximal tubule. In the present study, we overexpressed an intracellular cyan fluorescent ANG II fusion protein (Ad-sglt2-ECFP/ANG II) selectively in the proximal tubule of rats and mice using the sodium and glucose cotransporter 2 (sglt2) promoter. AGT mRNA and protein expression in the renal cortex and 24-h urinary AGT excretion were determined 4 wk following overexpression of ECFP/ANG II in the proximal tubule. Systolic blood pressure was significantly increased with a small antinatriuretic effect in rats and mice with proximal tubule-selective expression of ECFP/ANG II (P < 0.01). AGT mRNA and protein expression in the cortex were increased by >1.5-fold and 61 ± 16% (P < 0.05), whereas urinary AGT excretion was increased from 48.7 ± 5.7 (n = 13) to 102 ± 13.5 (n = 13) ng/24 h (P < 0.05). However, plasma AGT, renin activity, and ANG II levels remained unaltered by ECFP/ANG II. The increased AGT mRNA and protein expressions in the cortex by ECFP/ANG II were blocked in AT1a-knockout (KO) mice. Studies in cultured mouse proximal tubule cells demonstrated involvement of AT1a receptor/MAP kinases/NF-кB signaling pathways. These results indicate that intracellular ANG II stimulates AGT expression in the proximal tubules, leading to increased AGT formation and secretion into the tubular fluid, which contributes to ANG II-dependent hypertension.
authors: Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; and jzhuo@umc.edu.
authors: Jia L
authors: JL
authors: Zhuo
authors: Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana.
authors: H
authors: H
authors: Kobori
authors: Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; and.
authors: Xiao C
authors: XC
authors: Li
authors: Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana.
authors: R
authors: R
authors: Satou
authors: Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana.
authors: A
authors: A
authors: Katsurada
authors: Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana.
authors: L Gabriel
authors: LG
authors: Navar
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000808:Angiotensinogen / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure; D006973:Hypertension / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System; D012964:Sodium / Q000652:urine
chemical_list: D016328:NF-kappa B; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D000804:Angiotensin II; D012964:Sodium; D012083:Renin
keywords: NF-кB; angiotensin II; angiotensinogen; kidney; proximal tubule