Renin-angiotensin-aldosterone (RAAS): The ubiquitous system for homeostasis and pathologies

Coronavirus Disease 2019 and Hypertension: The Role of Angiotensin-Converting Enzyme 2 and the Renin-Angiotensin System.

R enin angiotensin system (RAS) antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists are increasingly used to treat cardiovascular and other diseases (1–6). These treatments induce a blockade of the RAS that may affect hemodynamics during anesthesia and surgery. In 1978, Miller et al. (7) reported that the RAS is involved in maintaining normal blood pressure during anesthesia. Although anesthesia is not invariably associated with a deleterious hemodynamic event in RAS-blocked patients (8–10), hemodynamic instability, described as unexpected episodes of hypotension, have been reported (11–13). Otherwise, stresses such as surgery or hypotension stimulate the generation of angiotensin II, which induces vasoconstriction (14) to maintain blood pressure but reduces blood flow to organs such as the kidneys and bowels. Accordingly, an angiotensin II-induced reduction in blood flow may contribute to acute renal failure (15) and splanchnic ischemia (16), which are obvious factors in postoperative morbidity (17). RAS blockade with ACE inhibitors decreases some consequences of the stress response on the regional circulation (9,18,19), which may then contribute to body protection. Much of the information regarding the physiology and pathophysiology of the RAS during anesthesia and surgery is based on the effects of ACE inhibitors. Because ACE inhibitors probably act mostly by blocking the RAS, similar effects should be obtained from angiotensin (AT) receptor antagonists. RAS antagonist pharmacology may help us to understand the hemodynamic risk of anesthesia in RAS-blocked patients, to identify predisposing factors, and to determine the potential benefit of RAS antagonists during anesthesia and surgery. Physiology of the RAS Generation of Angiotensin II

he prevalence of coronavirus disease 2019 (COVID-19) has posed a great threat to people's health worldwide, bringing a great challenges to the public healthcare systems. A recent study has confirmed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses severe acute respiratory syndrome coronavirus (SARS-CoV) receptor angiotensin-converting enzyme 2 (ACE2) for host cell entry. 1 ACE2 expression was previously found to correlate with susceptibility to SARS-CoV infection in vitro.

Objective: Hypertensive disorders of pregnancy (HDP) are a leading cause of maternal and infant morbidities and mortalities. Activity of the renin angiotensin aldosterone system (RAAS) is critical for the physiology of pregnancy, and suppressed RAAS during pregnancy is associated with adverse outcomes, such as preeclampsia. Obesity is a major contributor to adverse outcomes of pregnancy, and obesity modulates the RAAS in non-pregnant conditions. It is not known how the RAAS is regulated with obesity during pregnancy. We quantified serum biomarkers of the classical and alternative arms of the RAAS in a cohort of pregnant women to determine associations between obesity and activity of the RAAS during pregnancy. Design and Methods: We recruited a prospective cohort of n = 36 pregnant women in the first trimester with no clinical risk factors. Patients were separated into two groups, greater (n = 23) or less than (n = 13) body mass index (BMI) of 30 kg/m2 at enrollment. We quantified 6 angiotensin peptides, aldosterone, and enzyme activities of ACE2 and NEP in serum using LC-MS/MS in the first and third trimester. PRA, S was calculated as: Ang I + Ang II (pmol/L). Data are median [IQR]. Results: PRA, S and aldosterone increased with pregnancy in both groups, but the change from first to third trimester was reduced in the BMI > 30 group compared to those with BMI < 30 (PRA-S: 24.1 [-45.4 to 194.7] versus 70.9 [9.2 to 113.1]) pmol/L, respectively; Aldo: 234.3 [45.5 to 532.7] versus 648.2 [182.1 to 1207.3] pmol/L, respectively; P < 0.05). ACE2 activity was increased during pregnancy, with no differences between groups, however, NEP activity was elevated in the BMI > 30 group at both time points during pregnancy compared to the BMI < 30 group (1st trim: 13.4 [8.1 to 20.38] versus 8.4 [3.7 to 12.03]; 3rd trim: 21.3 [11.7 to 26.5] versus 13.47 [10.5 to 22.8] ng/mL; P < 0.01). In the BMI < 30 group, n = 2 developed gestational hypertension and n = 1 developed postpartum preeclampsia. In contrast, in the BMI > 30 group, n = 7 developed gestational hypertension, n = 2 developed preeclampsia/postpartum preeclampsia. Conclusion: Activity of the classical RAAS is reduced in women with 1st trimester BMI > 30 compared to those with BMI < 30. In contrast, the alternative RAS is not suppressed by obesity during pregnancy. Further, elevated 1st trimester BMI was associated with more adverse outcomes. Reduced activity of the classical RAAS with obesity may contribute to adverse outcomes in pregnancy.

ACE and ACE2: their role to balance the expression of angiotensin II and angiotensin-(1–7)

The Renin-Angiotensin-Aldosterone System (RAAS), which regulates plasma sodium levels, arterial blood pressure, and extracellular volume, is a crucial component of the human body. Angiotensin II is a multifunctional effector peptide hormone that is created when the renin enzyme, which is produced by the kidneys, interacts with angiotensinogen. RAAS activation and the ensuing hypertension, cell proliferation, inflammation, and fibrosis affect every organ. Numerous acute and chronic illnesses can be brought on by an imbalance between renin and angiotensin II. The advancement of kidney disease is correlated with proteinuria and a decline in renal function. RAAS over-activity promotes the emergence of a variety of clinical diseases, including the development of chronic kidney disease (CKD). In order to reduce blood pressure and proteinuria in patients with chronic kidney disease (CKD), reno preventive treatment has long depended on inhibiting the renin-angiotensin-aldosterone system (RAAS). According to research, RAAS inhibitors play a preventive effect in both the early and late stages of kidney disease by preventing proteinuria, kidney fibrosis, and slow decline in renal function. An overview of the RAAS pathway, its function in the kidney, and RAAS pathway blocking techniques for enhancing long-term outcomes in CKD patients are covered in this chapter.

Plasma Uric Acid (PUA), Renal Hemodynamic Function, and Arterial Stiffness at the Extremes of T1D Duration-Adolescents vs. Adults with T1D for =50 Years

Severe Acute Respiratory Syndrome Coronavirus-2 Cardiovascular Complications: Implications for Cardiothoracic Anesthesiology

A major hypothesisfor the development of hypertension is that abnormal renal excretory function is critical for the initiation, development, and maintenance of primary hypertension.1 The renal body fluid feedback mechanism couples the long-term regulation of arterial pressure to extracellular volume (sodium and water) homeostasis via pressure natriuresis, whereby the kidneys respond to changes in arterial pressure by altering urinary sodium and water excretion. The obligatory requirement for maintenance of sodium and water balance by the kidneys is believed to be primary in the long-term control of arterial pressure. An increase in arterial pressure (via increases in total peripheral resistance or cardiac output or both) leads to an increased urinary sodium and water excretion via the pressure natriuresis mechanism, with consequent reduction in blood volume until arterial pressure is returned to normal. Thus, factors that decrease renal excretory function and disrupt the maintenance of sodium and water balance by the kidneys lead to an increase in arterial pressure, which is required to reestablish and maintain sodium and water balance. Based on computer modeling studies, a long-term increase in arterial pressure can only occur if there is a chronic and sustained decrease in renal excretory function. Increased renal sympathetic nerve activity (RSNA) is known to be a factor capable of decreasing renal excretory function.2,3 The renal effects of increased RSNA include increased renal tubular sodium reabsorption leading to renal sodium retention; decreased renal blood flow and glomerular filtration rate with renal vasoconstriction and increased renal vascular resistance; and increased renin release leading to angiotensin II production. Each of these renal functional alterations can decrease renal excretory function. The role of increased RSNA as being a critically important factor contributing to this renal excretory dysfunction in hypertension is strengthened by the fact that increased RSNA has been identified in hypertensive human …

Preterm birth (< 37 gestational weeks) reaches 10% of total births worldwide. Early exposure to an ex utero environment can alter organogenesis and maturation in the newborn. This early onset of events can further promote long-term developmental alterations and cardiovascular disease risks. Mechanisms activated during preterm birth and promoting such cardiovascular alterations have just recently been investigated. As a major candidate, the renin angiotensin aldosterone system (RAAS) can be acutely altered during preterm birth and persistently activated in later life. Further, RAAS alterations may occur as consequence of kidney and heart immaturity to promote adaptive responses, suggesting a dual role of this system on fetal and neonatal organogenesis. Furthermore, fetal or neonatal exposure to deleterious stress conditions can significantly impact on this dual RAAS role, contributing to the establishment of hemodynamic and structural alterations. In this review, clinical and experimental findings describing RAAS components and activation in relationship with preterm birth are discussed. Further clinical and experimental investigations on RAAS activation in the context of preterm birth are needed to better understand this dual role of RAAS on early development and on programming of risks to cardiovascular diseases.

Hypertension Editors' Picks: Novel Drugs.

POINT:COUNTERPOINTThe dominant contributor to systemic hypertension: chronic activation of the sympathetic nervous system vs. activation of the intrarenal renin-angiotensin systemCounterpoint: Activation of the Intrarenal Renin-Angiotensin System is the Dominant Contributor to Systemic HypertensionL. Gabriel NavarL. Gabriel NavarChair, Department of Physiology Director, Center of Biomedical Research Excellence in Hypertension and Renal Biology Tulane University Health Sciences Center 1430 Tulane Avenue, SL39 New Orleans, LA 70112 e-mail: Published Online:01 Dec 2010https://doi.org/10.1152/japplphysiol.00182.2010aMoreSectionsPDF (137 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations Our discussion regarding the dominant mechanism responsible for hypertension calls to mind the famous poem, "The Blind Men and the Elephant," by John Godfrey Saxe based on an ancient fable from India. In essence, the blind men described the elephant based on their specific encounter, thus concluding that the elephant was a wall, a spear, a snake, a tree, a fan, or a rope. The lesson is that our interpretations regarding a specific experience are very much dependent on how it presented itself. Because of my predoctoral and postdoctoral training experiences with Arthur Guyton (10) and the fact that my research has been highly focused on the cardinal role of the kidneys in the pathophysiology of hypertension, I support the concept that alterations in kidney function in hypertension are predominantly due to an inappropriately increased activity of the intrarenal renin-angiotensin system (RAS; Refs. 12, 17, 19, 21). While the nervous system is important (4, 5), I contend that chronic activation of the sympathetic nervous system is not the dominant contributor to hypertension, but may also contribute to the activation of the intrarenal RAS that is characteristic of many forms of hypertension (3, 19, 22).Hypertension is characterized by increased peripheral vascular resistance due to increased vascular smooth muscle contractile activity and endothelial dysfunction (15, 29), but it is more likely that the vasculature is the victim rather than the culprit of the injurious processes that occur in hypertension (27). The nervous system regulates blood pressure by integrating signals coming from all parts of the body and sending neural signals to various organ systems. However, there is limited evidence that chronic increases in sympathetic activity serve as the dominant contributor to most forms of hypertension. Because the neurocentric view is being addressed by Esler, Lambert, and Schlaich (6), I will defer further consideration of this issue to them. Nevertheless, it is important to point out that the successful treatment of resistant hypertension using catheter-based renal sympathetic denervation was restricted to selected patients that were resistant to standard therapy (14).Through its multiple actions, the kidneys exert a predominant role to regulate arterial pressure (10, 12, 19, 24). Importantly, transplantation studies have demonstrated that the hypertension follows the kidneys (9). There are many models of experimental hypertension but most of them involve procedures or genetic manipulations that activate the RAS (8, 11, 13, 22, 23). While enhanced activity of renal sympathetic nerves contributes to the magnitude of the hypertension, the hypertensive response is only attenuated and the increases in intrarenal ANG II are similar in denervated kidneys as in innervated kidneys (11). In chronic ANG II-infused rabbits, the hypertension was not altered by renal denervation and renal sympathetic nerve activity was not changed (2). Furthermore, there was a general augmentation of vascular reactivity leading to augmented depressor responses to ganglionic blockade, but there was not an increased renal sympathetic activity (18). These studies have not shown differences in renal sympathetic nerve activity among rabbits with various forms of hypertension (2, 18). Prior renal denervation did not blunt the hypertension, suggesting that the sympathetic nervous system does not exert a direct role in the development of ANG II-induced hypertension (18).Derangements in kidney function that prevent maintenance of balance between salt excretion and salt intake vary from overt renal disease causing reduced excretory capability to transport derangements causing excess sodium reabsorption. Importantly, the studies of monogenetic diseases demonstrate that mutations associated with hypertension are consistently associated with altered tubular reabsorptive function (16). Liddle's syndrome, characterized by overactive amiloride sensitive sodium channels in the principal cells of collecting ducts, is a classic example (26). These single gene mutations demonstrate that transport alterations can cause hypertension independent of neural contributions. Although most forms of hypertension involve multiple gene effects, the final consequences are strikingly similar in that an inappropriate stimulation of tubular reabsorption leads to sodium retention and hypertension (19, 22, 26). Inappropriate activation of the intrarenal RAS is a very powerful hypertensinogenic mechanism because the pleiotropic actions of ANG II lead to increased renal vascular resistance, decreased renal blood flow, and glomerular filtration rate, increased aldosterone release and increased fractional sodium reabsorption at both proximal and distal nephron segments (12, 17, 20, 24, 30).Excess salt retention may also be caused by derangements in neurohormonal communication pathways that maintain normal renal function (19). When inappropriately activated, however, these signals may alter renal hemodynamics and/or tubular transport to prevent appropriate sodium excretion at normal arterial pressure. The excess salt and volume retention leads to increased arterial pressure which then elicits a pressure natriuresis response (Fig. 2), allowing the kidneys to restore sodium homeostasis but at the cost of an elevated arterial pressure (19, 22).Fig. 2.Pressure-natriuresis relationships and the responses to increases in salt intake or activation of the intrarenal renin-angiotensin system (RAS). Each pressure natriuresis relationship represents the acute responses in sodium excretion to changes in arterial pressure with all other systems maintained. The suppressed relationship occurs when there is overactivation of sodium retaining mechanisms such as increased RAS. The steeper curve represents the relationship when sodium retaining mechanisms are suppressed or sodium excretory mechanisms are activated such as with RAS inhibition or increased ANP. In normal individuals, a high salt intake leads to a shift in the pressure-natriuresis curve represented as arrow 1 such that sodium excretion increases with only small increases in arterial pressure. When the RAS is not appropriately suppressed, a high salt intake must lead to an increased arterial pressure to maintain sodium balance represented as arrow 2. If there is an augmented activation of the RAS, then even normal salt intake may require an increase in blood pressure to allow maintenance of sodium balance as depicted by arrow 3. While many other systems can modulate the magnitude of the responses, the final outcome always has to be the blood pressure where sodium balance can be maintained.Download figureDownload PowerPointThe RAS has a powerful role because it is both an intrarenal system and a powerful extrarenal system that influences essentially every organ system (20, 24). In addition to the liver, the proximal tubular cells also produce abundant angiotensinogen that help maintain intratubular and renal interstitial ANG II concentrations greater than those in the systemic circulation (12, 25, 28). Furthermore, renin is formed in cells of the juxtaglomerular apparatus and also in principal cells of the collecting ducts, allowing secretion into the tubular fluid to form ANG I from angiotensinogen derived from the proximal nephron (23–25). Thus, the ANG II-mediated increased vascular resistance along with increased tubular reabsorption mediated by an augmented intratubular RAS leads to a sustained decreased sodium excretion and hypertension (10, 19).An enhanced intrarenal RAS leads to enhanced ANG II throughout the body, thus contributing to increased cardiac contractility, increased peripheral vascular resistance, increased aldosterone release, and hypertensinogenic actions throughout the body (3, 12). Importantly, the pressure natriuresis mechanism, which is responsible for restoring sodium balance when there is inappropriate salt retention (10), does not escape the powerful influence of an augmented RAS (17, 19). As depicted in Fig. 2, augmented intrarenal ANG II levels suppress sodium excretion at any arterial pressure (17, 19). Nevertheless, with sufficient increases in arterial pressure, the increases in sodium excretion restore sodium balance, but again only at the expense of an elevated arterial pressure. The dominant role of the RAS in hypertension is reflected by the fact that blockade of the RAS with ACE inhibitors, ARBs, or the newer renin inhibitor is rapidly being recognized as one of the most effective antihypertensive therapeutic strategies (1, 7).Conclusion.In summary, many interacting physiological systems provide homeostatic regulation of arterial pressure, and derangements in any one of them can contribute to hypertension. While the nervous system provides regulatory inputs and stability to the blood pressure mechanisms, the primary responsibility for the long-term regulation of arterial pressure is vested in the kidneys' capability to integrate endocrine, neural, and hemodynamic inputs to maintain sodium balance and arterial blood pressure. Of the many mechanisms contributing to these alterations, the RAS axis plays a most vital role in regulating both sodium balance and blood pressure through its pleotropic actions on multiple vascular, endocrine, and renal mechanisms. Accordingly, it is the intrarenal/intratubular RAS that is the final dominant arbiter responsible for hypertension!GRANTSThe author's research has been supported by grants from National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, American Heart Association, and NCRR.ACKNOWLEDGMENTSI thank Debbie Olavarrieta for assistance in the preparation of the manuscript.REFERENCES1. Bakris GL , Toto RD , McCullough PA , Rocha R , Purkayastha D , Davis P. Effects of different ACE inhibitor combinations on albuminuria: results of the GUARD study. Kidney Int 73: 1303–1309, 2008.Crossref | PubMed | ISI | Google Scholar2. Burke SL , Evans RG , Moretti JL , Head GA. Levels of renal and extrarenal sympathetic drive in angiotensin II-induced hypertension. Hypertension 51: 878–883, 2008.Crossref | PubMed | ISI | Google Scholar3. Crowley SD , Gurley SB , Herrera MJ , Ruiz P , Griffiths R , Kumar AP , Kim HS , Smithies O , Le TH , Coffman TM. Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney. Proc Natl Acad Sci USA 103: 17985–17990, 2006.Crossref | PubMed | ISI | Google Scholar4. Davisson RL , Yang G , Beltz TG , Cassell MD , Johnson AK , Sigmund CD. The brain renin-angiotensin system contributes to the hypertension in mice containing both the human renin and human angiotensinogen transgenes. Circ Res 83: 1047–1058, 1998.Crossref | PubMed | ISI | Google Scholar5. DiBona GF. The sympathetic nervous system and hypertension: recent developments. Hypertension 43: 147–150, 2004.Crossref | PubMed | ISI | Google Scholar6. Esler M , Lampber E , Schlaich M. Point: Chronic activation of the sympathetic nervous system is the dominant contributor to systemic hypertension. J Appl Physiol; doi:10.1152/japplphysiol.00182.2010.ISI | Google Scholar7. Fisher ND , Hollenberg NK. Renin inhibition: what are the therapeutic opportunities? J Am Soc Nephrol 16: 592–599, 2005.Crossref | PubMed | ISI | Google Scholar8. Gonzalez-Villalobos RA , Seth DM , Satou R , Horton H , Ohashi N , Miyata K , Katsurada A , Tran DV , Kobori H , Navar LG. Intrarenal angiotensin II and angiotensinogen augmentation in chronic angiotensin II-infused mice. Am J Physiol Renal Physiol 295: F772–F779, 2008.Link | ISI | Google Scholar9. Guidi E , Menghetti D , Milani S , Montagnino G , Palazzi P , Bianchi G. Hypertension may be transplanted with the kidney in humans: a long-term historical prospective follow-up of recipients grafted with kidneys coming from donors with or without hypertension in their families. J Am Soc Nephrol 7: 1131–1138, 1996.Crossref | PubMed | ISI | Google Scholar10. Guyton AC. Blood pressure control—special role of the kidneys and body fluids. Science 252: 1813–1816, 1991.Crossref | PubMed | ISI | Google Scholar11. Ichihara A , Inscho EW , Imig JD , Michel RE , Navar LG. Role of renal nerves in afferent arteriolar reactivity in angiotensin-induced hypertension. Hypertension 29: 442–449, 1997.Crossref | PubMed | ISI | Google Scholar12. Kobori H , Nangaku M , Navar LG , Nishiyama A. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev 59: 251–287, 2007.Crossref | PubMed | ISI | Google Scholar13. Kobori H , Prieto-Carrasquero MC , Ozawa Y , Navar LG. AT1 receptor mediated augmentation of intrarenal angiotensinogen in angiotensin II-dependent hypertension. Hypertension 43: 1126–1132, 2004.Crossref | PubMed | ISI | Google Scholar14. Krum H , Schlaich M , Whitbourn R , Sobotka PA , Sadowski J , Bartus K , Kapelak B , Walton A , Sievert H , Thambar S , Abraham WT , Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 373: 1275–1281, 2009.Crossref | PubMed | ISI | Google Scholar15. Landmesser U , Cai H , Dikalov S , McCann L , Hwang J , Jo H , Holland SM , Harrison DG. Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 40: 511–515, 2002.Crossref | PubMed | ISI | Google Scholar16. Lifton RP , Gharavi AG , Geller DS. Molecular mechanisms of human hypertension. Cell 104: 545–556, 2001.Crossref | PubMed | ISI | Google Scholar17. Mitchell KD , Braam B , Navar LG. Hypertensinogenic mechanisms mediated by renal actions of renin-angiotensin system. Hypertension 19, Suppl I: I-18–I-27, 1992.Crossref | ISI | Google Scholar18. Moretti JL , Burke SL , Evans RG , Lambert GW , Head GA. Enhanced responses to ganglion blockade do not reflect sympathetic nervous system contribution to angiotensin II-induced hypertension. J Hypertens 27: 1838–1848, 2009.Crossref | PubMed | ISI | Google Scholar19. Navar LG , Hamm LL. The kidney in blood pressure regulation. In: Atlas of Diseases of the Kidney. Hypertension and the Kidney, edited by , Wilcox CS. Philadelphia: Current Medicine, 1999, p. 1.1–1.22.Google Scholar20. Navar LG , Harrison-Bernard LM , Imig JD , Mitchell KD. Renal actions of angiotensin II at AT1 receptor blockers. In: Angiotensin II Receptor Antagonists, edited by , Epstein M , Brunner HR. Philadelphia: Hanley & Belfus, 2000, p. 189–214.Google Scholar21. Navar LG , Harrison-Bernard LM , Nishiyama A , Kobori H. Regulation of intrarenal angiotensin II in hypertension. Hypertension 39: 316–322, 2002.Crossref | PubMed | ISI | Google Scholar22. Navar LG , Ploth DW. Pathophysiology of renovascular hypertension. In: Hypertension Primer: The Essentials of High Blood Pressure, edited by , Izzo JL , Black HR , Sica DA. Philadelphia: Lippincott Williams & Wilkins, 2008, p. 162–165.Google Scholar23. Prieto-Carrasquero MC , Botros FT , Pagan J , Kobori H , Seth DM , Casarini DE , Navar LG. Collecting duct renin is upregulated in both kidneys of 2-kidney, 1-clip Goldblatt hypertensive rats. Hypertension 51: 1590–1596, 2008.Crossref | PubMed | ISI | Google Scholar24. Prieto-Carrasquero MC , Kobori H , Navar LG. The intrarenal renin-angiotensin system. In: Hypertension and Hormone Mechanisms, edited by , Carey RM. Totowa, NJ: Humana, 2007, p. 3–22.Crossref | Google Scholar25. Rohrwasser A , Morgan T , Dillon HF , Zhao L , Callaway CW , Hillas E , Zhang S , Cheng T , Inagami T , Ward K , Terreros DA , Lalouel JM. Elements of a paracrine tubular renin-angiotensin system along the entire nephron. Hypertension 34: 1265–1274, 1999.Crossref | PubMed | ISI | Google Scholar26. Rossier BC , Schild L. Epithelial sodium channel: Mendelian versus essential hypertension. Hypertension 52: 595–600, 2008.Crossref | PubMed | ISI | Google Scholar27. Ruiz-Ortega M , Lorenzo O , Ruperez M , Esteban V , Suzuki Y , Mezzano S , Plaza JJ , Egido J. Role of the renin-angiotensin system in vascular diseases: expanding the field. Hypertension 38: 1382–1387, 2001.Crossref | PubMed | ISI | Google Scholar28. Schunkert H , Ingelfinger JR , Jacob H , Jackson B , Bouyounes B , Dzau VJ. Reciprocal feedback regulation of kidney angiotensinogen and renin mRNA expressions by angiotensin II. Am J Physiol Endocrinol Metab 263: E863–E869, 1992.Link | ISI | Google Scholar29. Touyz RM. The role of angiotensin II in regulating vascular structural and functional changes in hypertension. Curr Hypertens Rep 5: 155–164, 2003.Crossref | PubMed | ISI | Google Scholar30. Zhao D , Seth DM , Navar LG. Enhanced distal nephron sodium reabsorption in chronic angiotensin II-infused mice. Hypertension 54: 120–126, 2009.Crossref | PubMed | ISI | Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByDevelopment and validation of a nomogram model for individualized prediction of hypertension risk in patients with type 2 diabetes mellitus23 January 2023 | Scientific Reports, Vol. 13, No. 1Assessment of plasma catecholamines in patients with dysmetabolic iron overload syndromeJournal of Applied Biomedicine, Vol. 20, No. 4Screening of potential spike glycoprotein / ACE2 dual antagonists against COVID-19 in silico molecular dockingJournal of Virological Methods, Vol. 301The sympathies of the body: functional organization and neuronal differentiation in the peripheral sympathetic nervous system10 November 2021 | Cell and Tissue Research, Vol. 386, No. 3ANTIHYPERTENSIVE PHARMACOTHERAPY IN HYPERTENSIVE PATIENTS AT A TERTIARY CARE TEACHING HOSPITAL AND MEDICAL COLLEGE IN INDIA7 November 2021 | Asian Journal of Pharmaceutical and Clinical ResearchIdentification and action mechanism of low-molecular-weight peptides derived from Atlantic salmon (Salmo salar L.) skin inhibiting angiotensin I–converting enzymeLWT, Vol. 150Brain and kidney GHS-R1a underexpression is associated with changes in renal function and hemodynamics during neurogenic hypertensionMolecular and Cellular Endocrinology, Vol. 518Altered renal medullary blood flow: A key factor or a parallel event in control of sodium excretion and blood pressure?7 April 2020 | Clinical and Experimental Pharmacology and Physiology, Vol. 47, No. 8Interaction mechanism of egg white- derived ACE inhibitory peptide TNGIIR with ACE and its effect on the expression of ACE and AT1 receptorFood Science and Human Wellness, Vol. 9, No. 1Role of ACE2 Gene Expression in Renin Angiotensin System and Its Importance in Covid-19: In Silico Approach1 January 2020 | Brazilian Archives of Biology and Technology, Vol. 63Definition of hypertension‐associated oral pathogens in NHANES29 May 2019 | Journal of Periodontology, Vol. 90, No. 8Neuroimmune crosstalk in the pathophysiology of hypertension20 March 2019 | Nature Reviews Cardiology, Vol. 16, No. 8Plant-Based Ethnopharmacological Remedies for Hypertension in Suriname30 January 2019Morphological and Functional Characteristics of Blood and Lymphatic Vessels9 May 2019Evidence against a crucial role of renal medullary perfusion in blood pressure control of hypertensive rats10 November 2018 | The Journal of Physiology, Vol. 597, No. 1Median preoptic nucleus excitatory neurotransmitters in the maintenance of hypertensive stateBrain Research Bulletin, Vol. 142Influence of age and gender on blood pressure variability and baroreflex sensitivity in a healthy population in the Indian sub-continent14 July 2018 | Journal of Basic and Clinical Physiology and Pharmacology, Vol. 29, No. 4Hyperglycaemia induced by chronic i.p . and oral glucose loading leads to hypertension through increased Na + retention in proximal tubule7 December 2017 | Experimental Physiology, Vol. 103, No. 2Renin-angiotensin system inhibitors and risk of fractures: a prospective cohort study and meta-analysis of published observational cohort studies27 July 2017 | European Journal of Epidemiology, Vol. 32, No. 11Hemodynamic responses to mental stress during salt loading6 April 2016 | Clinical Physiology and Functional Imaging, Vol. 37, No. 6ACE inhibitors and the risk of fractures: a meta-analysis of observational studies19 December 2016 | Endocrine, Vol. 55, No. 3Normotension, hypertension and body fluid regulation: brain and kidney19 June 2016 | Acta Physiologica, Vol. 219, No. 1Different blood pressure responses to opioids in 3 rat hypertension models: role of the baseline status of sympathetic and renin–angiotensin systemsCanadian Journal of Physiology and Pharmacology, Vol. 94, No. 11Peroxisome proliferator-activated receptor-α stimulation by clofibrate favors an antioxidant and vasodilator environment in a stressed Reports, Vol. No. March 2016 | Experimental Physiology, Vol. No. regulation of blood pressure in and hypertension: when 2016 | Experimental Physiology, Vol. No. of the January 2016 | Current Hypertension Reports, Vol. No. occurs hypertension in the December | Experimental Physiology, Vol. No. of and in the long-term regulation of blood pressure and Kim G. Seth L. and December | American Journal of and Physiology, Vol. No. crosstalk between the kidney and the nervous system: the role of renal nerves in blood pressure January | Experimental Physiology, Vol. No. regulation of salt and a model of kidney function and pressure and January | American Journal of Physiology, Vol. No. elevated and enhanced sympathetic in of angiotensin II-infused hypertensive | The Journal of Physiology, Vol. No. be sympathetic to angiotensin II | The Journal of Physiology, Vol. No. vs. Physiology in the of A. | Physiology, Vol. No. sympathetic nervous system and blood pressure in humans: for July | Journal of Human Vol. No. of renal medullary blood in hypertensive evidence against April | Acta Physiologica, Vol. No. and of the Guyton of Blood of June | Vol. No. activation by stimulation of in and March | Journal of Applied Physiology, Vol. No. of Angiotensin for of the | Current Hypertension Reports, Vol. 13, No. in the nucleus the enhanced cardiac sympathetic afferent and sympathetic activity in renovascular hypertensive and March | Journal of Applied Physiology, Vol. No. 3 from this issue & the American Published 1 December Published in 1 December

Abstracts

Patients with chronic kidney disease (CKD) are prone to developing cardiac hypertrophy and fibrosis, which is associated with increased fibroblast growth factor 23 (FGF23) serum levels. Elevated circulating FGF23 was shown to induce left ventricular hypertrophy (LVH) via the calcineurin/NFAT pathway and contributed to cardiac fibrosis by stimulation of profibrotic factors. We hypothesized that FGF23 may also stimulate the local renin–angiotensin–aldosterone system (RAAS) in the heart, thereby further promoting the progression of FGF23-mediated cardiac pathologies. We evaluated LVH and fibrosis in association with cardiac FGF23 and activation of RAAS in heart tissue of 5/6 nephrectomized (5/6Nx) rats compared to sham-operated animals followed by in vitro studies with isolated neonatal rat ventricular myocytes and fibroblast (NRVM, NRCF), respectively. Uremic rats showed enhanced cardiomyocyte size and cardiac fibrosis compared with sham. The cardiac expression of Fgf23 and RAAS genes were increased in 5/6Nx rats and correlated with the degree of cardiac fibrosis. In NRVM and NRCF, FGF23 stimulated the expression of RAAS genes and induced Ngal indicating mineralocorticoid receptor activation. The FGF23-mediated hypertrophic growth of NRVM and induction of NFAT target genes were attenuated by cyclosporine A, losartan and spironolactone. In NRCF, FGF23 induced Tgfb and Ctgf, which were suppressed by losartan and spironolactone, only. Our data suggest that FGF23-mediated activation of local RAAS in the heart promotes cardiac hypertrophy and fibrosis.

Background and aimsIn this study, we investigated whether increased renin angiotensin aldosterone system (RAAS) activation and endothelin-1 levels are related to coronary artery calcium (CAC) score, total plaque volume (TPV), high risk plaque, hyperemic myocardial blood flow (MBF) and coronary microvascular dysfunction (CMD). MethodsIn a prospective, observational, cross-sectional cohort, renin as a marker for RAAS activation and endothelin-1 were measured in peripheral venous blood of 205 patients (64% men; age 58 ± 8.7 years) with suspected coronary artery disease (CAD) who underwent coronary computed tomography angiography (CCTA), [15O]H2O positron emission tomography (PET) perfusion imaging and invasive fractional flow reserve (FFR) measurements. Patients were categorized into three groups based on FFR (≤0.80) and hyperemic MBF <2.3 ml/min/g: [1] obstructive CAD (n = 92), [2] CMD (n = 26) or [3] no or non-obstructive CAD (n = 85). ResultsAfter correction for baseline characteristics, including RAAS inhibiting therapy, renin associated positively with CAC score and TPV, but not with hyperemic MBF (p < 0.01; p = 0.02 and p = 0.23). Patients with high risk plaque displayed higher levels of renin (mean logarithmic renin 1.25 ± 0.43 vs. 1.12 ± 0.35 pg/ml; p = 0.04), but not endothelin-1. Compared to no or non-obstructive CAD patients, renin was significantly elevated in obstructive CAD patients but not in CMD patients (mean logarithmic renin 1.06 ± 0.34 vs. 1.23 ± 0.36; p < 0.01 and 1.06 ± 0.34 vs. 1.16 ± 0.41 pg/ml; p = 0.65). Endothelin-1 did not differ between the three patient groups. ConclusionsOur report provides evidence that RAAS activity measured by renin concentration is elevated in patients with coronary atherosclerosis and high risk plaque but not in patients with CMD, whereas endothelin-1 is not related to either.