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Medicine Sep 2015Earlier published studies investigating the association between polymorphisms in the angiotensinogen gene and lung cancer risk showed no consistent results. In this... (Meta-Analysis)
Meta-Analysis Review
Earlier published studies investigating the association between polymorphisms in the angiotensinogen gene and lung cancer risk showed no consistent results. In this study, we have summarized all currently available data to examine the correlation by meta-analysis. Case-control studies addressing the association being examined were identified through Embase, the Cochrane Library, ISI Web of Science (Web of Knowledge), Google Scholar, PubMed, and CNKI databases. Risk of lung cancer (odds ratio [OR] and 95% confidence interval [CI]) was estimated with the fixed or the random effects model assuming homozygous, allele, heterozygous, dominant, and recessive models for all angiotensinogen polymorphisms. We identified a total of 10 articles in this meta-analysis, including 7 for Leu84Phe, 4 for Ile143Val, and 3 for Leu53Leu. In the meta-analysis of Leu84Phe polymorphism, the homozygous model provided an OR of 1.44 (Phe/Phe vs Ile/Ile: OR = 1.44, 95% CI = 1.04-1.99, P values for heterogeneity test (Q-test) [P(Het)] = 0.382). The significantly increased risk was similarly indicated in the recessive model (Phe/Phe vs Phe/Ile + Ile/Ile: OR = 1.41, 95% CI = 1.02-1.95, P(Het) = 0.381). We also observed a positive association in the Caucasian subgroup. The heterozygous model and the dominant model tested for the Ile143Val polymorphism showed a marginally increased risk (Ile/Val vs Ile/Ile: OR = 1.16, 95% CI = 1.00-1.36, P(Het) = 0.323; Val/Val + Ile/Val vs Ile/Ile: OR = 1.15, 95% CI = 0.99-1.34, P(Het) = 0.253). These data suggest that Leu84Phe and Ile143Val polymorphisms in the angiotensinogen gene may be useful biomarkers for lung cancer in some specific populations.
Topics: Angiotensinogen; Genetic Predisposition to Disease; Humans; Lung Neoplasms
PubMed: 26376373
DOI: 10.1097/MD.0000000000001250 -
Pharmacological Reviews Jul 2022The concept of local formation of angiotensin II in the kidney has changed over the last 10-15 years. Local synthesis of angiotensinogen in the proximal tubule has been... (Review)
Review
The concept of local formation of angiotensin II in the kidney has changed over the last 10-15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as megalin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. SIGNIFICANCE STATEMENT: Angiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation.
Topics: Female; Humans; Male; Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensinogen; Cardiovascular Diseases; Drug Delivery Systems; Kidney; Renin; Renin-Angiotensin System; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 35710133
DOI: 10.1124/pharmrev.120.000236 -
Molecular and Cellular Endocrinology Jun 2021Pregnancy demands major cardiovascular, renal and endocrine changes to provide an adequate blood supply for the growing fetus. The renin-angiotensin-aldosterone system... (Review)
Review
Pregnancy demands major cardiovascular, renal and endocrine changes to provide an adequate blood supply for the growing fetus. The renin-angiotensin-aldosterone system plays a key role in this adaptation process. One of its components, prorenin, is released in significant amounts from the ovary and uteroplacental unit. This review describes the sources of prorenin in the periconception period and in pregnancy, including its modulation by in-vitro fertilization protocols, and discusses its potential effects, among others focusing on preeclampsia. It ends with discussing the long-term consequences, even in later life, of inappropriate renin-angiotensin-aldosterone system activity in pregnancy and offers directions for future research. Ultimately, a full understanding of the role of prorenin periconceptionally and during pregnancy will help to develop tools to diagnose and/or prevent reproductive complications.
Topics: Angiotensin I; Angiotensinogen; Female; Fertilization in Vitro; Gene Expression Regulation; Humans; Ovary; Placenta; Pre-Eclampsia; Pregnancy; Renin; Renin-Angiotensin System; Signal Transduction; Uterus
PubMed: 33878417
DOI: 10.1016/j.mce.2021.111281 -
Clinical and Experimental Nephrology Dec 2018Renin-angiotensin-aldosterone system (RAAS) plays important roles in regulating renal hemodynamics and functions, as well as in the pathophysiology of hypertension and... (Review)
Review
Renin-angiotensin-aldosterone system (RAAS) plays important roles in regulating renal hemodynamics and functions, as well as in the pathophysiology of hypertension and renal disease. In the kidney, angiotensin II (Ang II) production is controlled by independent multiple mechanisms. Ang II is compartmentalized in the renal interstitial fluid with much higher concentrations than those existing in the circulation. Inappropriate activation of the intrarenal RAAS is an important contributor to the pathogenesis of hypertension and renal injury. It has been revealed that intrarenal Ang II levels are predominantly regulated by angiotensinogen and therefore, urinary angiotensinogen could be a biomarker for intrarenal Ang II generation. In addition, recent studies have demonstrated that aldosterone contributes to the progression of renal injury via direct actions on glomerular podocytes, mesangial cells, proximal tubular cells and tubulo-interstitial fibroblasts through the activation of locally expressed mineralocorticoid receptor. Thus, it now appears that intrarenal RAAS is independently regulated and its inappropriate activation contributes to the pathogenesis of the development of hypertension and renal disease. This short review article will focus on the independent regulation of the intrarenal RAAS with an emphasis on the specific role of angiotensinogen.
Topics: Angiotensin II; Angiotensinogen; Enzyme-Linked Immunosorbent Assay; Humans; Hypertension; Kidney; Kidney Diseases; Renin; Renin-Angiotensin System
PubMed: 29600408
DOI: 10.1007/s10157-018-1567-1 -
The Journal of Physiological Sciences :... Jul 2019Hypertension is one of the most important risk factors and a leading cause of death from cardiovascular and cerebrovascular diseases. Based on numerous previous studies,... (Review)
Review
Hypertension is one of the most important risk factors and a leading cause of death from cardiovascular and cerebrovascular diseases. Based on numerous previous studies, hypertension is thought to be caused by the complex mutual interactions of genetic factors and environmental factors, such as excessive salt intake and stress. However, its detailed mechanisms are not yet clearly understood. The renin-angiotensin system (RAS) is a key hormonal system in the pathogenesis of hypertension. New knowledge is still accruing on this cascade, even after more than 120 years since the discovery of renin. To clarify the molecular mechanisms of RAS in vivo, we created transgenic mice with chronic hypertension. These mice carry the human genes encoding renin, a hypertensive enzyme, and its substrate angiotensinogen. Hypotensive mice homozygous for a targeted disruption of the angiotensinogen gene were also created. This review presents our 47-year history of RAS research.
Topics: Angiotensinogen; Animals; Humans; Hypertension; Renin-Angiotensin System
PubMed: 31028527
DOI: 10.1007/s12576-019-00679-4 -
Hypertension (Dallas, Tex. : 1979) Oct 2022Multiple types of renin-angiotensin system (RAS) blockers exist, allowing interference with the system at the level of renin, angiotensin-converting enzyme, or the... (Review)
Review
Multiple types of renin-angiotensin system (RAS) blockers exist, allowing interference with the system at the level of renin, angiotensin-converting enzyme, or the angiotensin II receptor. Yet, in particular, for the treatment of hypertension, the number of patients with uncontrolled hypertension continues to rise, either due to patient noncompliance or because of the significant renin rises that may, at least partially, overcome the effect of RAS blockade (RAS escape). New approaches to target the RAS are either direct antisense oligonucleotides that inhibit angiotensinogen RNA translation, or small interfering RNA (siRNA) that function via the RNA interference pathway. Since all angiotensins stem from angiotensinogen, lowering angiotensinogen has the potential to circumvent the RAS escape phenomenon. Moreover, antisense oligonucleotides and small interfering RNA require injections only every few weeks to months, which might reduce noncompliance. Of course, angiotensinogen suppression also poses a threat in situations where the RAS is acutely needed, for instance in women becoming pregnant during treatment, or in cases of emergency, when severe hypotension occurs. This review discusses all preclinical data on angiotensinogen suppression, as well as the limited clinical data that are currently available. It concludes that it is an exciting new tool to target the RAS with high specificity and a low side effect profile. Its long-term action might revolutionize pharmacotherapy, as it could overcome compliance problems. Preclinical and clinical programs are now carefully investigating its efficacy and safety profile, allowing an optimal introduction as a novel drug to treat cardiovascular and renal diseases in due time.
Topics: Angiotensinogen; Female; Humans; Hypertension; Kidney Diseases; Oligonucleotides, Antisense; Pregnancy; RNA, Small Interfering; Renin; Renin-Angiotensin System
PubMed: 35904033
DOI: 10.1161/HYPERTENSIONAHA.122.18731 -
Kidney International Jan 2021Renin production by the kidney is of vital importance for salt, volume, and blood pressure homeostasis. The lack of human models hampers investigation into the...
Renin production by the kidney is of vital importance for salt, volume, and blood pressure homeostasis. The lack of human models hampers investigation into the regulation of renin and its relevance for kidney physiology. To develop such a model, we used human induced pluripotent stem cell-derived kidney organoids to study the role of renin and the renin-angiotensin system in the kidney. Extensive characterization of the kidney organoids revealed kidney-specific cell populations consisting of podocytes, proximal and distal tubular cells, stromal cells and endothelial cells. We examined the presence of various components of the renin-angiotensin system such as angiotensin II receptors, angiotensinogen, and angiotensin-converting enzymes 1 and 2. We identified by single-cell sequencing, immunohistochemistry, and functional assays that cyclic AMP stimulation induces a subset of pericytes to increase the synthesis and secretion of enzymatically active renin. Renin production by the organoids was responsive to regulation by parathyroid hormone. Subcutaneously implanted kidney organoids in immunodeficient IL2Ry/-Rag2 mice were successfully vascularized, maintained tubular and glomerular structures, and retained capacity to produce renin two months after implantation. Thus, our results demonstrate that kidney organoids express renin and provide insights into the endocrine potential of human kidney organoids, which is important for regenerative medicine in the context of the endocrine system.
Topics: Angiotensin II; Angiotensinogen; Animals; Endothelial Cells; Humans; Induced Pluripotent Stem Cells; Kidney; Mice; Organoids; Renin; Renin-Angiotensin System
PubMed: 32918942
DOI: 10.1016/j.kint.2020.08.008 -
Journal of the... 2019The most common disease associated with the presence of kidney cysts in the population is autosomal dominant polycystic kidney disease (ADPKD), which finally leads to...
BACKGROUND
The most common disease associated with the presence of kidney cysts in the population is autosomal dominant polycystic kidney disease (ADPKD), which finally leads to end-stage renal disease.
METHOD
The study evaluated serum and urinary concentration of angiotensinogen (AGT) and interleukin 18 (IL-18) in a group of 39 children with renal cysts of different aetiology.
RESULTS
Serum and urinary AGT concentration in children with renal cysts was higher compared to controls, regardless of the underlying background and gender. Serum IL-18 concentration was lower, in contrast, and the concentration of IL-18 in the urine did not differ between affected and healthy children. Negative correlation between urinary IL-18 concentration and systolic and mean arterial blood pressure was noted.
CONCLUSIONS
Higher AGT levels in serum and urine in children with renal cysts may indicate the activation of the renin-angiotensin-aldosterone system, including its intrarenal part, even before the onset of hypertension. Lower serum concentration of IL-18 in children with kidney cysts may indicate the loss of the protective role of this cytokine with the occurrence of hypertension.
Topics: Adolescent; Angiotensinogen; Biomarkers; Blood Pressure; Case-Control Studies; Child; Child, Preschool; Female; Glomerular Filtration Rate; Humans; Infant; Interleukin-18; Kidney Diseases, Cystic; Male; Young Adult
PubMed: 31379247
DOI: 10.1177/1470320319862662 -
International Journal of Molecular... Apr 2021Angiotensinogen (AGT) and aldosterone play key roles in the regulation of blood pressure and are implicated in the pathogenesis of cardiovascular diseases. DNA... (Review)
Review
Angiotensinogen (AGT) and aldosterone play key roles in the regulation of blood pressure and are implicated in the pathogenesis of cardiovascular diseases. DNA methylation typically acts to repress gene transcription. The aldosterone synthase gene is regulated by angiotensin II and potassium. DNA methylation negatively regulates and expression and dynamically changes in response to continuous promoter stimulation of each gene. High salt intake and excess circulating aldosterone cause DNA demethylation around the CCAAT-enhancer-binding-protein (CEBP) sites of the promoter region, thereby converting the phenotype of expression from an inactive to an active state in visceral adipose tissue and heart. A close association exists between low DNA methylation at CEBP-binding sites and increased expression in salt-sensitive hypertensive rats. Salt-dependent hypertension may be partially affected by increased cardiac expression. CpG dinucleotides in the promoter are hypomethylated in aldosterone-producing adenomas. Methylation of recognition sequences of transcription factors, including CREB1, NGFIB (NR4A1), and NURR1 (NR4A2) diminish their DNA-binding activity. The methylated CpG-binding protein MECP2 interacts directly with the methylated promoter. Low salt intake and angiotensin II infusion lead to upregulation of expression and DNA hypomethylation in the adrenal gland. Treatment with the angiotensin II type 1 receptor antagonist decreases expression and leads to DNA hypermethylation. A close association between low DNA methylation and increased expression are seen in the hearts of patients with hypertrophic cardiomyopathy. These results indicate that epigenetic regulation of both and contribute to the pathogenesis of cardiovascular diseases.
Topics: Aldosterone; Angiotensin II; Angiotensinogen; CCAAT-Enhancer-Binding Proteins; Cardiovascular Diseases; Cytochrome P-450 CYP11B2; DNA Methylation; Epigenesis, Genetic; Gene Expression; Gene Expression Regulation; Humans; Hypertension; Promoter Regions, Genetic; Transcription Factors
PubMed: 33925539
DOI: 10.3390/ijms22094587 -
American Journal of Physiology. Renal... Oct 2022Components of the renin-angiotensin system, including angiotensinogen (AGT), are critical contributors to chronic kidney disease (CKD) development and progression....
Components of the renin-angiotensin system, including angiotensinogen (AGT), are critical contributors to chronic kidney disease (CKD) development and progression. However, the specific role of tissue-derived AGTs in CKD has not been fully understood. To define the contribution of liver versus kidney AGT in the CKD development, we performed 5/6 nephrectomy (Nx), an established CKD model, in wild-type (WT), proximal tubule (PT)- or liver-specific AGT knockout (KO) mice. Nx significantly elevated intrarenal AGT expression and elevated blood pressure (BP) in WT mice. The increase of intrarenal AGT protein was completely blocked in liver-specific AGT KO mice with BP reduction, suggesting a crucial role for liver AGT in BP regulation during CKD. Nx-induced glomerular and kidney injury and dysfunction, as well as fibrosis, were all attenuated to a greater extent in liver-specific AGT KO mice compared with PT-specific AGT KO and WT mice. However, the suppression of interstitial fibrosis in PT- and liver-specific AGT KO mouse kidneys was comparable. Our findings demonstrate that liver AGT acts as a critical contributor in driving glomerular and tubular injury, renal dysfunction, and fibrosis progression, whereas the role of PT AGT was limited to interstitial fibrosis progression in chronic renal insufficiency. Our results provide new insights for the development of tissue-targeted renin-angiotensin system intervention in the treatment of CKD. Chronic kidney disease (CKD) is a major unmet medical need with no effective treatment. Current findings demonstrate that hepatic and proximal tubule angiotensinogen have distinct roles in tubular and glomerular injury, fibrogenesis, and renal dysfunction during CKD development. As renin-angiotensin system components, including angiotensinogen, are important targets for treating CKD in the clinic, the results from our study may be applied to developing better tissue-targeted treatment strategies for CKD and other fibroproliferative diseases.
Topics: Angiotensinogen; Animals; Fibrosis; Kidney; Liver; Mice; Renal Insufficiency; Renal Insufficiency, Chronic; Renin-Angiotensin System
PubMed: 35924445
DOI: 10.1152/ajprenal.00029.2022