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Current Opinion in Pharmacology Apr 2011The increased activity of intrarenal renin-angiotensin system (RAS) in a setting of elevated arterial pressure elicits renal vasoconstriction, increased sodium... (Review)
Review
The increased activity of intrarenal renin-angiotensin system (RAS) in a setting of elevated arterial pressure elicits renal vasoconstriction, increased sodium reabsorption, proliferation, fibrosis and renal injury. Increases in intrarenal and interstitial angiotensin (Ang) II levels are due to increased AT(1) receptor mediated Ang II uptake and stimulation of renal angiotensinogen (AGT) mRNA and protein expression. Augmented proximal tubule AGT production increases tubular AGT secretion and spillover of AGT into the distal nephron and urine. Increased renin formation by principal cells of the collecting ducts forms Ang I from AGT thus increasing Ang II. The catalytic actions of renin and prorenin are enhanced by prorenin receptors (PRRs) on the intercalated cells. The resultant increased intrarenal Ang II levels contribute to the genesis of chronic hypertension.
Topics: Angiotensin II; Angiotensinogen; Animals; Chronic Disease; Humans; Hypertension; Kidney; Kidney Tubules, Collecting; Receptors, Cell Surface; Renin; Prorenin Receptor
PubMed: 21339086
DOI: 10.1016/j.coph.2011.01.009 -
Journal of the... 2022We assessed the relationship between AGT gene M235T polymorphism and the susceptibility to cancer by performing an updated meta-analysis. This study retrospectively... (Meta-Analysis)
Meta-Analysis Review
We assessed the relationship between AGT gene M235T polymorphism and the susceptibility to cancer by performing an updated meta-analysis. This study retrospectively searched related articles in the electronic databases. Afterwards, we determined combined odds ratios (ORs) and related 95% confidence intervals (CIs) by the fixed- or random-effects model. The present meta-analysis enrolled altogether 9 articles. On the whole, the relationship between AGT M235T polymorphism and the cancer risk was not significant among the entire population (TT vs. MM: OR = 1.28, 95%CI = 0.80 - 2.04; TM vs. MM: OR = 0.90, 95%CI = 0.53 - 1.52; recessive model: OR = 1.13, 95%CI = 0.83 - 1.52; dominant model: OR = 0.93, 95%CI = 0.55 - 1.57). Subgroup analysis by ethnicity, cancer type, and study quality for the relationship between the AGT M235T polymorphism and cancer risk showed no significant association. According to findings in the present meta-analysis, AGT M235T polymorphism may not be related to cancer susceptibility.
Topics: Angiotensinogen; Genetic Predisposition to Disease; Humans; Neoplasms; Polymorphism, Genetic; Retrospective Studies
PubMed: 35317386
DOI: 10.1155/2022/7862709 -
Current Opinion in Nephrology and... Jan 2013Although the existence of a complete intrarenal renin-angiotensin system is now well established, its role in modulating tubule sodium transport and blood pressure is... (Review)
Review
PURPOSE OF REVIEW
Although the existence of a complete intrarenal renin-angiotensin system is now well established, its role in modulating tubule sodium transport and blood pressure is incompletely understood. Several recent studies have shed light on one component of the system, proximal tubule-derived angiotensinogen (AGT). This review discusses the synthesis, regulation and function of AGT in the proximal tubule.
RECENT FINDINGS
Under normal sodium intake, AGT within the S1 and S2 segments of the proximal tubule may derive from the systemic circulation, whereas the S3 segment synthesizes AGT. Urinary AGT likely primarily reflects proximal tubule-derived AGT. Proximal tubule AGT synthesis is regulated by high Na intake, angiotensin-II and inflammatory cytokines. Transgenic expression of mouse AGT in the proximal tubule causes hypertension. Overexpression of rat AGT in the proximal tubule leads to hypertension, enhanced reactive oxygen species generation via NADPH oxidase, tubular apoptosis and tubulointerstitial fibrosis; these effects can be mitigated by catalase overexpression.
SUMMARY
Proximal tubule-derived AGT has the potential to modulate blood pressure and sodium balance, and promote renal injury. Interactions with the systemic renin-angiotensin system may influence the role of proximal tubule-derived AGT in the kidney.
Topics: Angiotensinogen; Animals; Blood Pressure; Homeostasis; Humans; Hypertension; Kidney Tubules, Proximal; Sodium; Water
PubMed: 23010762
DOI: 10.1097/MNH.0b013e328359dbed -
Journal of the... 2018Preeclampsia (PE) is a pregnancy-associated hypertensive disorder and a leading cause of maternal and neonatal morbidity and mortality. While its pathogenesis remains...
BACKGROUND
Preeclampsia (PE) is a pregnancy-associated hypertensive disorder and a leading cause of maternal and neonatal morbidity and mortality. While its pathogenesis remains ill defined, several candidate genes for PE have been identified, but results remain inconclusive. We investigated the association of the angiotensinogen ( AGT) gene variants M235T and T174M with PE, and we analyzed the contribution of both variants to the severity of PE.
METHODS
This case-control study enrolled 550 Tunisian pregnant women: 272 with PE, of whom 147 presented with mild, and 125 with severe PE, along with 278 unrelated age- and ethnically matched control women. AGT genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism.
RESULTS
Significantly higher M235T minor allele frequency (MAF) was associated with increased risk of PE ( p < 0.001). Decreased frequency of heterozygous T174M genotype carriers were found in control women ( p = 0.015), suggesting a protective effect of this genotype (odds ratio (95% confidence interval) = 0.51 (0.29-0.89)). Two-locus haplotype analysis demonstrated MM and TT haplotypes to be negatively and positively associated with PE, respectively. MAF of M253T, but not T174M, was higher in the severe PE group, and carrying M235T or T174M minor allele was associated with increased body mass index ( p < 0.001) among unselected PE women.
CONCLUSIONS
AGT M235T and T174M variants contribute to an increased risk of developing PE, and for M235T to PE severity.
Topics: Adult; Alleles; Angiotensinogen; Case-Control Studies; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Polymorphism, Single Nucleotide; Pre-Eclampsia; Pregnancy; Severity of Illness Index; Tunisia
PubMed: 29366364
DOI: 10.1177/1470320317753924 -
Scientific Reports Jul 2023Inappropriate activation of intrarenal renin-angiotensin system (RAS) may contribute to the pathogenesis of cardio-renal syndrome (CRS). We aimed to examine the...
Inappropriate activation of intrarenal renin-angiotensin system (RAS) may contribute to the pathogenesis of cardio-renal syndrome (CRS). We aimed to examine the cross-sectional associations of urinary angiotensinogen (AGT) excretion, a biomarker of intrarenal RAS activity, with central (aortic) and renal hemodynamic parameters in middle-aged and older adults, including patients with chronic kidney disease. Aortic and renal hemodynamic parameters were measured using applanation tonometry and duplex ultrasonography in 282 participants. Urinary AGT, liver-type fatty acid-binding protein (L-FABP), and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were measured for each participant. Multiple linear regression analyses demonstrated that urinary AGT levels were associated with aortic blood pressures, pulsatile measures of renal blood flow, plasma NT-proBNP and urinary L-FABP levels after adjusting for potential covariates, including age, sex, body mass index, estimated glomerular filtration rate (GFR), and medication use. Additionally, when classified based on GFR stages and urinary AGT levels, plasma NT-proBNP and urinary L-FABP levels increased in participants with lower GFR and higher AGT groups. Our findings suggest that urinary AGT excretion is a shared determinant of central (aortic) and renal hemodynamics in middle-aged and older adults, providing clinical evidence for the potential role of intrarenal RAS activity in the development of CRS.
Topics: Middle Aged; Humans; Aged; Angiotensinogen; Cross-Sectional Studies; Kidney; Renin-Angiotensin System; Renal Insufficiency, Chronic
PubMed: 37460637
DOI: 10.1038/s41598-023-38507-w -
Journal of Gastrointestinal and Liver... Mar 2016Angiotensin II (AII) is a powerful splanchnic vasoconstrictor with pro-inflammatory and pro-fibrotic properties. Angiotensin converting enzyme (ACE) inhibitors and AII... (Observational Study)
Observational Study
BACKGROUND AND AIMS
Angiotensin II (AII) is a powerful splanchnic vasoconstrictor with pro-inflammatory and pro-fibrotic properties. Angiotensin converting enzyme (ACE) inhibitors and AII Receptor Antagonists (ARBs) are therapeutic in animal models of colitis. The aim of this case-control study is to determine the expression of angiotensinogen and related genes in human ileal Crohn's disease.
METHODS
Using quantitative real-time polymerase chain reaction (RT-PCR), we measured mRNA expression levels of angiotensinogen (AGT), hypoxia inducible factor (HIF)1α and melanoma cell adhesion molecule (MCAM; CD146) in 101 human samples (69 biopsy, 12 resection) from affected ileum (inflamed CD cases, n=36) and unaffected ileum (non-inflamed CD cases, n=45 and controls, n=20). Immunohistochemistry for angiotensinogen was also performed. The study was of case-control design in a tertiary care setting.
RESULTS
Ileal expression of AGT was lower in CD cases compared to controls (p<0.0001), in inflamed CD samples (p=0.017) and current smokers (p=0.02). HIF1α expression was lower in non-inflamed CD biopsy samples than controls (p=0.006). The presence of disease-associated NOD2 variants was associated with increased expression of markers of angiogenesis (HIF1α p=0.009; MCAM p=0.007) in inflamed CD samples. Angiotensinogen immunohistochemical staining supported the quantitative RT-PCR expression findings.
CONCLUSIONS
Angiotensinogen expression is down regulated in human ileal CD, particularly in the presence of inflammation and current cigarette smoking, implicating the mesenteric vasculature and mucosal hypoxia as co-factors in ileal CD pathogenesis. A novel reduction in HIF1α expression in non-inflamed ileal mucosa in CD patients was also demonstrated.
Topics: Adult; Aged; Angiogenic Proteins; Angiotensinogen; CD146 Antigen; Case-Control Studies; Crohn Disease; Female; Gene Expression Regulation; Genotype; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Ileum; Immunohistochemistry; Male; Middle Aged; Neovascularization, Pathologic; Nod2 Signaling Adaptor Protein; Phenotype; RNA, Messenger; Real-Time Polymerase Chain Reaction; Smoking; Young Adult
PubMed: 27014752
DOI: 10.15403/jgld.2014.1121.251.chr -
American Journal of Physiology. Renal... Aug 2016In angiotensin II (ANG II)-dependent hypertension, there is an angiotensin type 1 receptor-dependent amplification mechanism enhancing intrarenal angiotensinogen (AGT)...
In angiotensin II (ANG II)-dependent hypertension, there is an angiotensin type 1 receptor-dependent amplification mechanism enhancing intrarenal angiotensinogen (AGT) formation and secretion in the tubular fluid. To evaluate the role of increased arterial pressure, AGT mRNA, protein expression, and urinary AGT (uAGT) excretion and tissue injury were assessed in both kidneys of two-kidney, one-clip Sprague-Dawley hypertensive rats subjected to left renal arterial clipping (0.25-mm gap). By 18-21 days, systolic arterial pressure increased to 180 ± 3 mmHg, and uAGT increased. Water intake, body weights, 24-h urine volumes, and sodium excretion were similar. In separate measurements of renal function in anesthetized rats, renal plasma flow and glomerular filtration rate were similar in clipped and nonclipped kidneys and not different from those in sham rats, indicating that the perfusion pressure to the clipped kidneys remained within the autoregulatory range. The nonclipped kidneys exhibited increased urine flow and sodium excretion. The uAGT excretion was significantly greater in nonclipped kidneys compared with clipped and sham kidneys. AGT mRNA was 2.15-fold greater in the nonclipped kidneys compared with sham (1.0 ± 0.1) or clipped (0.98 ± 0.15) kidneys. AGT protein levels were also greater in the nonclipped kidneys. The nonclipped kidneys exhibited greater glomerular expansion and immune cell infiltration, medullary fibrosis, and cellular proliferation than the clipped kidneys. Because both kidneys have elevated ANG II levels, the greater tissue injury in the nonclipped kidneys indicates that an increased arterial pressure synergizes with increased intrarenal ANG II to stimulate AGT production and exert greater renal injury.
Topics: Angiotensinogen; Animals; Arterial Pressure; Body Weight; Drinking; Fibrosis; Hypertension, Renovascular; Immunity, Cellular; Kidney; Kidney Glomerulus; Kidney Medulla; Male; RNA, Messenger; Rats; Rats, Sprague-Dawley; Sodium
PubMed: 27194718
DOI: 10.1152/ajprenal.00419.2015 -
Clinical Science (London, England :... Jul 2018The renin-angiotensin system (RAS) is widely recognized as one of the most important vasoactive hormonal systems in the physiological regulation of blood pressure and... (Review)
Review
The renin-angiotensin system (RAS) is widely recognized as one of the most important vasoactive hormonal systems in the physiological regulation of blood pressure and the development of hypertension. This recognition is derived from, and supported by, extensive molecular, cellular, genetic, and pharmacological studies on the circulating (tissue-to-tissue), paracrine (cell-to-cell), and intracrine (intracellular, mitochondrial, nuclear) RAS during last several decades. Now, it is widely accepted that circulating and local RAS may act independently or interactively, to regulate sympathetic activity, systemic and renal hemodynamics, body salt and fluid balance, and blood pressure homeostasis. However, there remains continuous debate with respect to the specific sources of intratubular and intracellular RAS in the kidney and other tissues, the relative contributions of the circulating RAS to intratubular and intracellular RAS, and the roles of intratubular compared with intracellular RAS to the normal control of blood pressure or the development of angiotensin II (ANG II)-dependent hypertension. Based on a lecture given at the recent XI International Symposium on Vasoactive Peptides held in Horizonte, Brazil, this article reviews recent studies using mouse models with global, kidney- or proximal tubule-specific overexpression (knockin) or deletion (knockout) of components of the RAS or its receptors. Although much knowledge has been gained from cell- and tissue-specific transgenic or knockout models, a unifying and integrative approach is now required to better understand how the circulating and local intratubular/intracellular RAS act independently, or with other vasoactive systems, to regulate blood pressure, cardiovascular and kidney function.
Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Disease Models, Animal; Humans; Kidney; Kidney Tubules, Proximal; Liver; Mice; Renin; Renin-Angiotensin System
PubMed: 29986878
DOI: 10.1042/CS20180121 -
Kidney International Dec 1994Recent evidence suggests the involvement of a local renin-angiotensin system in some renal actions of angiotensin II (Ang II). In this study the renal distribution of... (Comparative Study)
Comparative Study
Recent evidence suggests the involvement of a local renin-angiotensin system in some renal actions of angiotensin II (Ang II). In this study the renal distribution of the precursor to angiotensin formation, angiotensinogen, was investigated in rats and sheep using immunohistochemistry, immunoelectron microscopy and non-isotopic hybridization histochemistry. Immunostaining for angiotensinogen was seen in proximal tubules (PCT) of both rat and sheep kidneys. In the rat the strongest immunostaining was found in the kidneys of neonatal (1 day old) rats. Staining declined after birth. Non-isotopic hybridization histochemistry using oligodeoxynucleotide probes labeled with biotin confirmed the presence of angiotensinogen mRNA expression in PCT of the rat renal cortex. Electron microscopic immunohistochemistry using antibodies raised against rat angiotensinogen showed weak staining in the adult of granule-like structures close to the apical membrane of PCT cells. In the neonatal rat kidney, angiotensinogen immunostaining was found throughout the PCT cells and was markedly stronger than that seen in adult rat kidney. In sheep, angiotensinogen immunostaining with an antibody raised against purified ovine angiotensinogen showed staining of PCT in fetal, newborn and adult sheep kidney. The strongest immunostaining seen was in fetal sheep kidney with a decline seen after birth. Reverse transcription polymerase chain reaction (RT-PCR) showed that angiotensinogen mRNA was expressed in the sheep kidney at all ages studied. Angiotensinogen expression was higher in fetal sheep kidneys (77 day and 141 day gestation) than in adult sheep kidney. In conclusion, angiotensinogen mRNA expression was detected in both rat and sheep kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Angiotensinogen; Animals; Animals, Newborn; Fetus; Immunohistochemistry; Kidney; Microscopy, Immunoelectron; RNA, Messenger; Rats; Renin-Angiotensin System; Sheep
PubMed: 7700005
DOI: 10.1038/ki.1994.445 -
Bioscience Reports Jan 2019Angiotensinogen (AGT) is the unique substrate of all angiotensin peptides. We review the recent preclinical research of AGT antisense oligonucleotides (ASOs), a rapidly... (Review)
Review
Angiotensinogen (AGT) is the unique substrate of all angiotensin peptides. We review the recent preclinical research of AGT antisense oligonucleotides (ASOs), a rapidly evolving therapeutic approach. The scope of the research findings not only opens doors for potentially new therapeutics of hypertension and many other diseases, but also provides insights into understanding critical physiological and pathophysiological roles mediated by AGT.
Topics: Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Drug Evaluation, Preclinical; Genetic Therapy; Humans; Hypertension; Kidney; Liver; Molecular Targeted Therapy; Oligonucleotides, Antisense; Rats, Inbred SHR; Renin-Angiotensin System
PubMed: 30530571
DOI: 10.1042/BSR20180201