AT<sub>1</sub> receptor-mediated augmentation of angiotensinogen, oxidative stress, and inflammation in ANG II-salt hypertension

Lara, Lucienne S.; McCormack, Michael; Semprum-Prieto, Laura C.; Shenouda, Sylvia K.; Majid, Dewan S. A.; Kobori, Hiroyuki; Navar, L. Gabriel; Prieto, Minolfa C.

doi:10.1152/ajprenal.00351.2011

Cited by 72 publications

(116 citation statements)

References 48 publications

(66 reference statements)

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“…It has been shown that augmentation of intra-renal AGT synthesis, secretion, and excretion is associated with the development of hypertension, renal oxidative stress, and tissue injury. 32 Therefore, the changes which occurred in the expression of AGT and its receptor AT-1 in the CYP-administered group were due to alteration in oxidative stress and tissue injury reported in renal histology and controlled by SO co-administration.…”

Section: Discussionmentioning

confidence: 95%

Genetic and histopathological alterations induced by cypermethrin in rat kidney and liver: Protection by sesame oil

Soliman

Attia

2015

Int J Immunopathol Pharmacol

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Pesticides are widespread synthesized substances used for public health protection and agricultural programs. However, they cause environmental pollution and health hazards. This study aimed to examine the protective effects of sesame oil (SO) on the genetic alterations induced by cypermethrin (CYP) in the liver and kidney of Wistar rats. Male rats were divided into four groups, each containing 10 rats: the control group received vehicle, SO group (5 mL/kg b.w), CYP group (12 mg/kg b.w), and protective group received SO (5 mL/kg b.w) plus CYP (12 mg/kg b.w). Biochemical analysis showed an increase in albumin, urea, creatinine, GPT, GOT, and lipid profiles in the CYP group. Co-administration of SO with CYP normalized such biochemical changes. CYP administration decreased both the activity and mRNA expression of the examined antioxidants. SO co-administration recovered CYP, downregulating the expression of glutathione-S-transferase (GST), catalase, and superoxide dismutase. Additionally, SO co-administration with CYP counteracted the CYP- altering the expression of renal interleukins (IL-1 and IL-6), tumor necrosis factor alpha (TNF-α), heme oxygenase-1 (HO-1), anigotensinogen (AGT), AGT receptors (AT1), and genes of hepatic glucose and fatty acids metabolism. CYP induced degenerative changes in the kidney and liver histology which are ameliorated by SO. In conclusion, SO has a protective effect against alterations and pathological changes induced by CYP in the liver and kidney at genetic and histological levels.

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Section: Discussionmentioning

confidence: 95%

Genetic and histopathological alterations induced by cypermethrin in rat kidney and liver: Protection by sesame oil

Soliman

Attia

2015

Int J Immunopathol Pharmacol

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“…Our studies further suggest that internalized (or intracellular) ANG II may act on cytoplasmic and nuclear AT 1 receptors to induce longterm transcriptional effects on the RAS (33, 34). Second, there is increasing evidence suggesting that ANG II may be generated intrarenally, especially in the proximal tubules and collecting ducts during ANG II-induced hypertension (11,16,22,44). Indeed, we and others have shown that chronic infusion of ANG II is associated with marked increases in angiotensinogen (AGT) expression in the renal cortex and urinary AGT excretion, which is also AT 1 receptor dependent (11,16,22,44).…”

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confidence: 99%

Augmentation of angiotensinogen expression in the proximal tubule by intracellular angiotensin II via AT_1a/MAPK/NF-кB signaling pathways

Zhuo

Kobori

et al. 2016

American Journal of Physiology-Renal Physiology

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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 Ͻ 0.01). AGT mRNA and protein expression in the cortex were increased by Ͼ1.5-fold and 61 Ϯ 16% (P Ͻ 0.05), whereas urinary AGT excretion was increased from 48.7 Ϯ 5.7 (n ϭ 13) to 102 Ϯ 13.5 (n ϭ 13) ng/24 h (P Ͻ 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-B 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.angiotensin II; angiotensinogen; kidney; NF-B; proximal tubule THE IMPORTANT ROLE OF THE renin-angiotensin system (RAS), especially its major effector peptide, angiotensin II (ANG II), in the development and maintenance of hypertension has been well established in all ANG II-dependent hypertension models, including two-kidney, one-clip (2K1C) (5, 30, 46), Ren-2 gene transgenic (40,42,59), and ANG II-infused animals (7,56,61,63). One important and consistent feature of these ANG II-dependent hypertension models is that ANG II levels in the kidneys are increased to a greater extent than can be explained on the basis of elevated plasma ANG II which suppresses renin expression in the juxtaglomerular apparatus (JGA) of the kidney (12,29,44,61). The mechanisms underlying this phenomenon remain incompletely understood. Currently, there are at least two potential mechanisms contributing to augmentation of ANG II levels in the kidney: AT 1 receptor-mediated angiotensinogen (AGT) expression and uptake of circulating ANG II by the proximal tubules. We and others have shown that circulating ANG II or systemically infused ANG II is taken up and accumulated in the proximal tubule of the kidney, including endosomal, mitochondrial, and nuclear compartments (1,15,29,47,61). The uptake of circulating ANG II by the proximal tubule of the kidney appears to be med...

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“…24 Although Matsusaka et al confirm that AGT in the urine is derived, in large part, from the mRNA encoding AGT present in latter segments of the proximal tubules, these levels are extremely low and can be markedly upregulated to yield many fold greater increases in urinary AGT concentrations as found in AII-infused animals. 21,24,30 Urinary AII levels are markedly augmented when there is a stimulus for AGT overexpression in renal proximal tubules, demonstrating that AGT produced in proximal tubules contributes to intrarenal AII elevation and increased urinary AGTexcretion. 31 Thus, the study by Matsusaka et al does not address contributions of intrarenal mRNA encoding AGT and locally synthesized AGT to tubular AII in AII-dependent hypertension or in various kidney diseases.…”

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The Increasing Complexity of the Intratubular Renin-Angiotensin System

Satou

2012

Journal of the American Society of Nephrology

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The presence of receptors for angiotensin II (AII) on the luminal membranes of various nephron segments has been well established for many decades.1,2 Originally their function remained unclear because tubular fluid AII concentrations were thought to be quite low due to the presence of various degrading enzymes on the brush border of proximal tubular cells. However, a series of reports in the 1990s demonstrated that the proximal tubular concentrations of AI and AII are in the nanomolar range and much higher than can be explained by tubular fluid reabsorption or equilibration with the circulating levels. 3,4 These findings led to a paradigm shift in our concepts regarding the role of luminal AII receptors in various nephron segments, and it is now well accepted that intraluminal AII and other angiotensin peptides exert various actions on transport systems in essentially all nephron segments predominantly through activation of AT1 receptors. 5-10In further studies, proximal tubular fluid samples were incubated with excess renin to determine substrate availability. The resultant AI concentrations demonstrated that the proximal tubular fluid angiotensinogen (AGT) concentrations are also very high 11 and greater than the circulating concentrations, indicating that it is unlikely the tubular AGT concentrations are derived from filtered AGT, in particular considering the limited permeability of the AGT because of its large size.11 Using in situ perfusion of proximal tubules with artificial tubular fluid with the delivery of filtrate blocked, Braam et al.4 collected the tubular fluid from downstream segments and found these also had elevated AII concentrations in the nanomolar range, supporting tubular secretion of AII or its precursors. Studies on isolated perfused tubules from S2 segments indicated that AII is produced intracellularly and secreted preformed into the tubular lumen, supporting the presence of intact AGT in isolated proximal tubule segments.12 These findings, along with clear evidence for the presence of AGT mRNA and protein in proximal tubular cells, [13][14][15] provided the foundation for the concept that the intratubular AII concentrations are derived primarily from locally synthesized substrate. The local production of AGT in the proximal tubule was supported by Terada et al., 14 who demonstrated the presence of a large signal for AGTmRNA in microdissected proximal convoluted and straight tubules. In vitro studies have also consistently demonstrated mRNA encoding AGT in proximal tubular cell lines extracted from proximal tubule segments.15,16 However, Pohl et al. 17 recently reported predominant localization of mRNA encoding AGT to S3 segments.The findings of kidney tubular mRNA encoding AGT notwithstanding, the kidney's ability to produce AGT is dwarfed by that of the liver, the organ primarily responsible for the maintenance of circulating AGT concentrations. In addition, it is well recognized that filtered AGT can be taken up by proximal tubule scavenger receptors such as megalin and cubilin, ...

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AT₁ receptor-mediated augmentation of angiotensinogen, oxidative stress, and inflammation in ANG II-salt hypertension

Cited by 72 publications

References 48 publications

Genetic and histopathological alterations induced by cypermethrin in rat kidney and liver: Protection by sesame oil

Genetic and histopathological alterations induced by cypermethrin in rat kidney and liver: Protection by sesame oil

Augmentation of angiotensinogen expression in the proximal tubule by intracellular angiotensin II via AT_1a/MAPK/NF-кB signaling pathways

The Increasing Complexity of the Intratubular Renin-Angiotensin System

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AT1 receptor-mediated augmentation of angiotensinogen, oxidative stress, and inflammation in ANG II-salt hypertension

Cited by 72 publications

References 48 publications

Genetic and histopathological alterations induced by cypermethrin in rat kidney and liver: Protection by sesame oil

Genetic and histopathological alterations induced by cypermethrin in rat kidney and liver: Protection by sesame oil

Augmentation of angiotensinogen expression in the proximal tubule by intracellular angiotensin II via AT1a/MAPK/NF-кB signaling pathways

The Increasing Complexity of the Intratubular Renin-Angiotensin System

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AT₁ receptor-mediated augmentation of angiotensinogen, oxidative stress, and inflammation in ANG II-salt hypertension

Augmentation of angiotensinogen expression in the proximal tubule by intracellular angiotensin II via AT_1a/MAPK/NF-кB signaling pathways