Renal Renin Secretion Research Articles

#5849 RENAL RENIN IS UPREGULATED BY THE COMBINATION TREATMENT OF EMPAGLIFLOZIN AND RAS BLOCKADE IN EXPERIMENTAL DIABETIC NEPHROPATHY

Abstract Background and Aims Sodium-glucose cotransporter 2 (SGLT2) inhibitors have proven to delay diabetic nephropathy (DN) progression on top of renin-angiotensin system (RAS) blockade. This protection is mainly attributed to improvement in renal hemodynamics, although direct effects on the kidney cannot be ruled out. The present study aimed to identify renal proteins differentially expressed between vehicle-treated diabetic mice and mice treated with empagliflozin, ramipril, or their combination, that could help explain the protective mechanisms of the drugs. Method Twelve weeks old diabetic db/db mice were given empagliflozin (10 mg/Kg/day), ramipril (8 mg/Kg/day), or the combination of both drugs during 8 weeks. Vehicle-treated db/db and db/m mice were used as controls. Serum glucose, blood pressure, GFR, and albuminuria were measured at baseline and at the end of the study. After 8 weeks, mice were euthanized, and the kidneys and serum were saved. A differential high-throughput proteomic analysis by mass spectrometry using isobaric tandem mass tags (TMT labelling) was performed in kidney cortex. Results Vehicle-treated db/db mice showed increased glycemia during the whole experiment, and empagliflozin reduced blood glucose. Ramipril treatment decreased blood pressure. Vehicle-treated diabetic mice also showed incipient DN with increased mesangial matrix and albuminuria compared to their non-diabetic littermates. All the treatments reduced mesangial matrix expansion and albuminuria. Only 13 proteins were differentially expressed (false discovery rate <5% and Log2FC ≥1 or ≤ −1) when comparing treated mice vs vehicle-treated db/db mice. The differentially expressed proteins were only identified between the mice treated with the combination of empagliflozin and ramipril and the vehicle-treated diabetic mice. Ramipril or empagliflozin alone did not produce significant changes in renal proteins. Kidney renin was evidently increased by the combination therapy with empagliflozin and ramipril, along with the tubular transporter scaffolding protein MAP17. The results were further validated through renin staining and renal renin concentration measurement. Renal renin concentration was increased by ramipril and further increased by the combination therapy with empagliflozin and ramipril when compared to vehicle-treated db/db mice (55 pg/μg (IQR:49–64), 94 pg/μg (IQR:71–102), and 112 pg/μg (IQR 104–116) in the groups treated with vehicle, ramipril and the combination of empagliflozin and ramipril respectively). However, renin serum concentration was similar between mice treated with ramipril and mice treated with the combination. Conclusion The combined therapy of empagliflozin with ramipril upregulated renin in the kidney of a diabetic mouse model. The increase in kidney renin suggests that other mechanisms different from RAS act in the regulation of glomerular hemodynamics and arteriolar tone. Moreover, the increased sodium delivery to the macula densa does not inhibit renal renin secretion.

Connexin mRNA distribution in adult mouse kidneys

Kidneys are thought to express eight different connexin isoforms (i.e., Cx 26, 30, 32, 37, 40, 43, 45, and 46), which form either hemichannels or gap junctions serving to intercellular communication and functional synchronization. Proper function of connexins has already been shown to be crucial for regulation of renal hemodynamics and renin secretion, and there is also growing evidence for connexins to play a role in pathologic conditions such as renal fibrosis or diabetic nephropathy. Therefore, exact intrarenal localization of the different connexin isoforms gains particular interest. Until now intrarenal expression of connexins has mainly been examined by immunohistochemistry, which in part generated conflicting results depending on antibodies and fixation protocols used. In this work, we used fluorescent RNAscope as an alternative technical approach to localize renal connexin mRNAs in healthy mouse kidneys. Addition of RNAscope probes for cell type specific mRNAs was used to assign connexin mRNA signals to specific cell types. We hereby found Cx26 mRNA strongly expressed in proximal tubules, Cx30 mRNA was selectively detected in the urothelium, and Cx32 mRNA was found in proximal tubules and to a lesser extent also in collecting ducts. Cx37 mRNA was mainly associated with vascular endothelium, Cx40 mRNA was largely found in glomerular mesangial and less in vascular endothelial cells, Cx43 mRNA was sparsely expressed by interstitial cells of all kidney zones, and Cx45 mRNA was predominantly found in smooth muscle cell layers of both blood vessels and ureter as well as in mesangial and interstitial (fibroblastic) cells. Cx46 mRNA could not be detected. In summary our results essentially confirm previous data on connexin expression in the renal vasculature and in glomeruli. In addition, they demonstrate strong connexin gene expression in proximal tubules, and they suggest significant connexin expression in resident tubulointerstitial cells.

Role of protease-activated receptor 2 in regulation of renin synthesis and secretion in mice.

It has been reported that the serine protease kallikrein stimulates and that aprotinin, a protease inhibitor, inhibits renal renin secretion. Since direct stimulation of the protease-activated receptor (PAR) 2 increases renin secretion in isolated perfused mouse kidneys, we hypothesized that activation of PAR2 receptors by serine proteases could be involved in the synthesis and secretion of renin in vivo. We therefore determined the response of plasma renin concentration (PRC) to acute intraperitoneal administration of the PAR2 agonist SLIGRL, isoproterenol, hydralazine, furosemide, losartan, or lipopolysaccharide in conscious wild-type (WT) and Par2-deficient mice. Basal PRC was not different in Par2-deficient mice compared with WT mice. All six acute treatments caused significant increases of PRC in both WT and Par2-deficient mice. The response was significantly lower only in endotoxin-treated Par2-deficient mice. Chronic treatment with losartan, low salt intake, the combination of both, or furosemide caused an increase of PRC and renin mRNA in WT mice, whereas a high salt intake caused a decrease. Alterations in PRC and renal renin mRNA expression were not different between WT and Par2 -/- mice in response to chronic treatments. Par2-deficiency did not alter furosemide-induced diuresis and natriuresis. Systolic blood pressure responses to chronic treatments were not different between WT and Par2 -/- mice. In conclusion, deficiency of Par2 receptors does not alter renin secretion and renin gene expression modulated by a variety of typical maneuvers. However, activation of Par2 receptors by serine proteases seems to be of importance for renin secretion in the context of inflammation.

Renal hemodynamics and renin-angiotensin system activity in humans with multifocal renal artery fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is the second most common cause of renovascular hypertension. Nonetheless, knowledge on the renal microvasculature and renin-angiotensin system (RAS) activity in kidneys with FMD is scarce. Given the fairly good results of revascularization, we hypothesized that the renal microvasculature and RAS are relatively spared in kidneys with FMD. In 58 hypertensive patients with multifocal renal artery FMD (off medication) and 116 matched controls with essential hypertension, we measured renal blood flow (Xenon washout method) per kidney and drew blood samples from the aorta and both renal veins to determine renin secretion and glomerular filtration rate per kidney. We found that renal blood flow and glomerular filtration rate in FMD were comparable to those in controls. Although systemic renin levels were somewhat higher in FMD, renal renin secretion was not elevated. Moreover, in patients with unilateral FMD, no differences between the affected and unaffected kidney were observed with regard to renal blood flow, glomerular filtration rate, or renin secretion. In men, renin levels and renin secretion were higher as compared with women. The renal blood flow response to RAS modulation (by intrarenal infusion of angiotensin II, angiotensin-(1-7), an angiotensin II type 1 receptor blocker, or a nitric oxide synthase blocker) was also comparable between FMD and controls. Renal blood flow, glomerular filtration, and the response to vasoactive substances in kidneys with multifocal FMD are comparable to patients with essential hypertension, suggesting that microvascular function is relatively spared. Renin secretion was not increased and the response to RAS modulation was not affected in kidneys with FMD.

Angiotensinergic innervation of the kidney: Localization and relationship with catecholaminergic postganglionic and sensory nerve fibers.

We describe an angiotensin (Ang) II-containing innervation of the kidney. Cryosections of rat, pig and human kidneys were investigated for the presence of Ang II-containing nerve fibers using a mouse monoclonal antibody against Ang II (4B3). Co-staining was performed with antibodies against synaptophysin, tyrosine 3-hydroxylase, and dopamine beta-hydroxylase to detect catecholaminergic efferent fibers and against calcitonin gene-related peptide to detect sensory fibers. Tagged secondary antibodies and confocal light or laser scanning microscopy were used for immunofluorescence detection. Ang II-containing nerve fibers were densely present in the renal pelvis, the subepithelial layer of the urothelium, the arterial nervous plexus, and the peritubular interstitium of the cortex and outer medulla. They were infrequent in central veins and the renal capsule and absent within glomeruli and the renal papilla. Ang II-positive fibers represented phenotypic subgroups of catecholaminergic postganglionic or sensory fibers with different morphology and intrarenal distribution compared to their Ang II-negative counterparts. The Ang II-positive postganglionic fibers were thicker, produced typically fusiform varicosities and preferentially innervated the outer medulla and periglomerular arterioles. Ang II-negative sensory fibers were highly varicose, prevailing in the pelvis and scarce in the renal periphery compared to the rarely varicose Ang II-positive fibers. Neurons within renal microganglia displayed angiotensinergic, catecholaminergic, or combined phenotypes. Our results suggest that autonomic fibers may be an independent source of intrarenal Ang II acting as a neuropeptide co-transmitter or neuromodulator. The angiotensinergic renal innervation may play a distinct role in the neuronal control of renal sodium reabsorption, vasomotion and renin secretion.

Renal renin secretion as regulator of body fluid homeostasis

The renin-angiotensin system is essential for body fluid homeostasis and blood pressure regulation. This review focuses on the homeostatic regulation of the secretion of active renin in the kidney, primarily in humans. Under physiological conditions, renin secretion is determined mainly by sodium intake, but the specific pathways involved and the relations between them are not well defined. In animals, renin secretion is a log-linear function of sodium intake. Close associations exist between sodium intake, total body sodium, extracellular fluid volume, and blood volume. Plasma volume increases by about 1.5mL/mmol increase in daily sodium intake. Several lines of evidence indicate that central blood volume may vary substantially without measurable changes in arterial blood pressure. At least five intertwining feedback loops of renin regulation are identifiable based on controlled variables (blood volume, arterial blood pressure), efferent pathways to the kidney (nervous, humoral), and pathways operating via the macula densa. Taken together, the available evidence favors the notion that under physiological conditions (1) volume-mediated regulation of renin secretion is the primary regulator, (2) macula densa mediated mechanisms play a substantial role as co-mediator although the controlled variables are not well defined so far, and (3) regulation via arterial blood pressure is the exception rather than the rule. Improved quantitative analyses based on in vivo and in silico models are warranted.

Blood pressure and renin–angiotensin system resetting in transgenic rats with elevated plasma Val5-angiotensinogen

Increases in plasma angiotensinogen (Ang-N) due to genetic polymorphisms or pharmacological stimuli like estrogen have been associated with a blood pressure (BP) rise, increased salt sensitivity and cardiovascular risk. The relationship between Ang-N, the resetting of the renin-angiotensin system, and BP still remains unclear. Angiotensin (Ang) II-induced genetic hypertension should respond to lisinopril treatment. A new transgenic rat line (TGR) with hepatic overexpression of native (rat) Ang-N was established to study high plasma Ang-N. The transgene contained a mutation producing Val(5)-Ang-II, which was measured separately from nontransgenic Ile-Ang-II in plasma and renal tissue. Male homozygous TGR had increased plasma Ang-N (~20-fold), systolic BP (ΔBP+26 mmHg), renin activity (~2-fold), renin activity/concentration (5-fold), total Ang-II (~2-fold, kidney 1.7-fold) but decreased plasma renin concentrations (-46%, kidney -85%) and Ile(5)-Ang-I and II (-93%, -94%) vs. controls. Heterozygous TGR exhibited ~10-fold higher plasma Ang-N and 17 mmHg ΔBP. Lisinopril decreased their SBP (-23 vs. -13 mmHg in controls), kidney Ang-II/I (~3-fold vs. ~2-fold) and Ile(5)-Ang-II (-70 vs. -40%), and increased kidney renin and Ile(5)-Ang-I (>2.5-fold vs. <2.5-fold). Kidney Ang-II remained higher and renin lower in TGR compared with controls. High plasma Ang-N increases plasma and kidney Ang-II levels, and amplifies the plasma and renal Ang-II response to a given change in renal renin secretion. This enzyme-kinetic amplification dominates over the Ang-II mediated feedback reduction of renin secretion. High Ang-N levels thus facilitate hypertension via small increases of Ang II and may influence the effectiveness of renin-angiotensin system inhibitors.

Angiotensin receptor-associated proteins: local modulators of the renin–angiotensin system

The activity of the renin-angiotensin system crucially depends on the rate of renal renin secretion. Changes in renin secretion result in fluctuations of angiotensin II concentrations in the circulation and subsequently in the activation of angiotensin receptors in all accessible target organs. Consequently, various mechanisms have evolved to regulate the local sensitivity to angiotensin II. In this review, an overview of angiotensin II receptor-associated proteins is addressed. These proteins regulate the local sensitivity of receptor-expressing cells by modulating the receptor surface expression and the receptor sensitivity. A hypothesis will be discussed that integrates the existence of various angiotensin receptor-associated proteins into an overall functional model.

Vitamin D zur Prävention von Erkrankungen?

Vitamin D3 shows a multitude of possible preventive effects in various diseases. Calcitriol, the biologically active form of vitamin D3, affects not only bone metabolism but also acts on the renal renin secretion, the pancreatic insulin production in the beta cells, growth and proliferation of smooth and cardiac muscle cells and the function of lymphocytes and macrophages. Although the human body can synthesise vitamin D3 itself, vitamin D deficiency is common in the German population. Numerous trials studied the association between vitamin D deficiency and different diseases. It is known that even mild forms of vitamin D deficiency increase the risk for cardiovascular diseases or diabetes mellitus. Furthermore, an association with cancer such as pancreatic or colorectal cancer was observed. This is attributed to the influence of vitamin D on cell differentiation, angiogenesis, DNA repair mechanisms and the transcription of numerous genes. In addition, effects of vitamin D deficiency in diseases such as Parkinson's disease, multiple sclerosis and autoimmune diseases are discussed. However, up to now the level of evidence of all these observations is low. There are missing confirmatory randomized controlled trials. Noting the possible preventive effects of vitamin D, a moderate exposure to sunlight to increase vitamin D synthesis can be recommended. Even a controlled supplementation of vitamin D in patients with vitamin D deficiency is considered as reasonable. However, an uncritical substitution of high-dose vitamin D should be avoided because of the risk of hypercalcaemia.

Proteinase-Activated Receptors 1 and 2 Exert Opposite Effects on Renal Renin Release

Proteinase-activated receptors (PARs) 1 to 4 are highly expressed in the kidney and are involved in the regulation of renal hemodynamics and tubular function. Since intravascular infusion of the proteinase thrombin, which activates PARs, has been shown to decrease plasma renin activity in rats, we investigated the effects of the respective PAR subtypes on renin release using the isolated perfused mouse kidney model. Thrombin dose-dependently reduced perfusate flow and inhibited renin secretion rates (RSRs) that had been prestimulated by the β-adrenoreceptor agonist isoproterenol. The suppression of RSRs was prevented by the selective PAR1 inhibitor SCH79797, and direct activation of PAR1 by TFLLR mimicked the effects of thrombin on RSRs and vascular tone. Moreover, TFLLR suppressed the stimulations of RSRs in response to the loop diuretic bumetanide, to prostaglandin E(2), or to a decrease in renal perfusion pressure but not in response to a reduction in extracellular calcium. The PAR2-activating peptide SLIGRL concentration dependently increased RSR and perfusate flow. The stimulation of RSRs by SLIGRL was markedly attenuated by N(G)-nitro-L-arginine methyl ester, suggesting an NO-dependent mechanism. Activation of PAR4 by AYPGKF did not modulate RSRs or perfusate flow. PAR1 and PAR2 immunoreactivity were detected in the juxtaglomerular region and were colocalized with renin immunoreactivity. Our data provide evidence that PAR1 activation inhibits renal renin secretion and induces renal vasoconstriction, whereas PAR2 activation stimulates renin release and induces vasodilation mainly via the release of NO.

More about plasma renin and cardiovascular mortality

This editorial refers to ‘Association of plasma renin with 10-year cardiovascular mortality, sudden cardiac death, and death due to heart failure’, by A. Tomaschitz et al. doi:10.1093/eurheartj/ehr150. Renin, the renal pressor substance, was discovered and described by Tigerstedt and Bergman in classic experiments published in 1898. It was not, however, until 1934 that Goldblatt identified the relevance of renin by showing that renal secretion of renin caused sustained renovascular hypertension in dogs. Others subsequently demonstrated that renin itself is not the pressor element, but rather is the rate-limiting component of the newly defined renin–angiotensin–aldosterone control system (RAAS).1 This RAAS has since become recognized as a key regulator of blood pressure control and a participating factor in its pathological consequences. In the past half century, the role of the RAAS in the pathophysiology of hypertension and as a basis for antihypertensive drug development was established.2,3 Plasma renin has also been associated with cardiovascular morbidity and mortality in hypertensive patients ( Figure 1 ).4,5 Tomaschitz et al. have now extended that finding to patients in whom plasma renin was measured while taking antihypertensive drugs.6 Figure 1 Adapted by permission from Macmillan Publishers Ltd: American Journal of Hypertension , Michael H. Alderman, Wee Lock Ooi, Hillel Cohen, Shantha Madhavan, Jean E. Sealey, John H. Laragh, Plasma renin activity: a risk factor for myocardial infarction in hypertensive patients, copyright (1997). Tomaschitz et al. measured the plasma renin concentration (PRC) using a sensitive automated immunoreactive chemiluminscence method that is comparable with the more traditional enzyme kinetic radioimmunoassay renin activity (PRA) assay. An exception is …

Comments on Point:Counterpoint: The dominant contributor to systemic hypertension: Chronic activation of the sympathetic nervous system vs. Activation of the intrarenal renin-angiotensin system

Comments on Point:Counterpoint: The dominant contributor to systemic hypertension: Chronic activation of the sympathetic nervous system vs. Activation of the intrarenal renin-angiotensin system

Effect of Angiotensin II Type 1 receptor blocker, Candesartan, and β1adrenoceptor blocker, Atenolol, on brain damage in ischemic stroke

This work aims at studying the possible alteration of renal renin secretion after human ischemic stroke and correlating it to the post stroke neurological and renal function alterations using angiotensin II type 1(AT1) receptor blocker (ARB), candesartan, and beta 1 adrenoreceptor blocker atenolol, which inhibits renin secretion, in Wistar rats subjected to middle cerebral artery occlusion. Methods . This study comprised 21 patients with cerebral ischemic stroke. Seventeen normal persons were used for comparison. Recumbent and standing plasma renin activity (PRA), reflex plasma renin sensitivity, plasminogen activator inhibitor and creatinine clearance (Ccr) were estimated at admission and two weeks later. Moreover, 60 male Wistar rats were divided into two groups SHAM and ischemic. Each of the two groups was further subdivided into three subgroups, non-treated, atenolol treated, and candesartan treated. In all rats, mean arterial blood pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), heart rate (HR), neurobehavioral evaluation, Ccr, PRA, and infarct size were measured. Results . Together with the significant deterioration of the neurological score, focal cerebral ischemia in rats resulted in increased PRA and decreased glomerular filtration rate (GFR). In ischemic stroke patients, GFR was significantly decreased at admission and two weeks later, PRA increased at admission and two weeks later while plasma renin reflex secretion sensitivity had decreased significantly at admission relative to controls, but it increased significantly 2 weeks later. Atenolol caused significant improvement of the neurobehavioral score and renal function and decrease infarct size of rats subjected to focal cerebral ischemia whereas candesartan caused significant improvement of the neurobehavioral score and decreased infarct size with no significant change in GFR. Neither atenolol nor candesartan caused significant change in MAP, SBP, DBP, PP and HR Conclusion . (1) Ischemic stroke seems to be associated with a postischemic increase of the plasma renin secretion, which may increase the infarct size in the brain and may induce acute renal insufficiency. (2) This study confirms that Atenolol and ARBs could benefit ischemic stroke patients without altering blood pressure.

It Is the Plasma Renin Activity Level That Counts, not Stoichiometry

HomeHypertensionVol. 52, No. 2It Is the Plasma Renin Activity Level That Counts, not Stoichiometry Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBIt Is the Plasma Renin Activity Level That Counts, not Stoichiometry Jean E. Sealey John H. Laragh Jean E. SealeyJean E. Sealey Department of Medicine, Weil Cornell Medical College, New York, NY Search for more papers by this author John H. LaraghJohn H. Laragh Department of Cardiothoracic Surgery, Weil Cornell Medical College and New York, Presbyterian Hospital, New York, NY Search for more papers by this author Originally published7 Jul 2008https://doi.org/10.1161/HYPERTENSIONAHA.108.116319Hypertension. 2008;52:e20Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 7, 2008: Previous Version 1 To the Editor:We disagree with Danser et al1 that, in patients taking the renin inhibitor aliskiren, “it is the stoichiometry that counts, not the rise in renin.” In fact, plasma renin activity (PRA) is a more explicit indicator than stoichiometry. A PRA fall during aliskiren means that renal renin secretion did not increase by much. A PRA rise means that the increase in renal renin secretion was large enough to overwhelm the aliskiren blockade of PRA. It is that simple.PRA falls during aliskiren therapy in most patients with mild-to-moderate hypertension2 (Figure). However, the magnitude of the fall differs among patients, and PRA actually increases in ≈1 in 20 patients, indicating that aliskiren can be overwhelmed by a reactive rise in renin.3 Moreover, 2 patients reported by Stanton et al2 had >20 mm Hg sustained increases in daytime systolic pressure (measured by ambulatory blood pressure monitoring), thereby indicating that blood pressure can rise during aliskiren. Download figureDownload PowerPointFigure. Medium/high renin patients had PRA >0.3 ng/mL per hour. (The Nussberger assay generates angiotensin I more slowly than the Sealey assay.) Patients with mild-to-moderate hypertension were treated for 4 weeks with 150 mg (triangles) or 300 mg (circles) of aliskiren. Vertical line=1 SD from the median value.Redrawn from Stanton et al.2A rise in blood pressure during aliskiren can alert the clinician to excessive kidney renin secretion; such a patient is likely to respond to a β-blocker, because β-blockers reduce renin secretion. However, there are 2 quite different reasons for the absence of a blood pressure fall during aliskiren. The patient may have had low renin to begin with and no renin to block, or, alternatively, renin secretion may have increased so much that it overcame the blocking action of the drug. PRA will be low in the former type of patient but not in the latter. The low-renin patient is likely to respond to a natriuretic drug,4 whereas adding a natriuretic drug instead of an antirenin drug to the hyperreactive renin patient will increase renin secretion even more to reduce the likelihood of a fall in blood pressure. Thus, knowing the PRA level is what counts, not stoichiometry.Sources of FundingThis work was supported by the May and Samuel Rudin Family Foundation, the Trust of Frederick Schwartz, and the Lawrence M. Gelb Foundation.DisclosuresJ.E.S. and J.H.L. are consultants to Diasorin Inc. J.H.L. has licensed patent 09/657.027, “Method for Evaluating and Treating Hypertension,” to Diasorin Inc.1 Danser AHJ, Charney A, Feldman DL, Nussberger J, Fisher N, Hollenberg N. The renin rise with aliskiren: it’s simple stoichiometry. Hypertension. 2008; 51: e27–e28.LinkGoogle Scholar2 Stanton A, Jensen C, Nussberger J, O'Brien E. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension. 2003; 42: 1137–11433.LinkGoogle Scholar3 Sealey JE, Laragh JH. Aliskiren, the first renin inhibitor for treating hypertension: reactive renin secretion may limit its usefulness. Am J Hypertens. 2007; 20: 587–597.CrossrefMedlineGoogle Scholar4 Laragh JH. Laragh’s lessons in pathophysiology and clinical pearls for treating hypertension. Lesson XVI. How to choose the correct drug treatment for each hypertensive patient using a plasma renin based method and volume vasoconstriction analysis. Am J Hypertens. 2001; 14: 491–503.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByStanton A, Gradman A, Schmieder R, Nussberger J, Sarangapani R and Prescott M (2009) Aliskiren Monotherapy Does Not Cause Paradoxical Blood Pressure Rises, Hypertension, 55:1, (54-60), Online publication date: 1-Jan-2010. Chaudhary K, Nistala R and Whaley-Connell A (2010) Is there a future for direct renin inhibitors?, Expert Opinion on Investigational Drugs, 10.1517/13543781003781906, 19:5, (653-661), Online publication date: 1-May-2010. Nussberger J, Stanton A, Fisher N, Hollenberg N and Jan Danser A (2008) Response to It Is the Plasma Renin Activity Level That Counts, not Stoichiometry, Hypertension, 52:2, (e21-e21), Online publication date: 1-Aug-2008. August 2008Vol 52, Issue 2 Advertisement Article InformationMetrics https://doi.org/10.1161/HYPERTENSIONAHA.108.116319PMID: 18606895 Originally publishedJuly 7, 2008 PDF download Advertisement SubjectsClinical StudiesDiagnostic TestingPharmacology

Mechanisms of Sympathetic Activation in Obesity-Related Hypertension

Obesity prevalence is soaring in industrialized countries and progressively increasing in the developing world. Altered patterns of nutrition and reduction in work-related energy expenditure have led to obesity becoming a truly global health issue. The central thermodynamic formulation for the origins of obesity, a mismatched energy balance equation, with an excess of dietary calorie intake over body energy expenditure, is a first step in the understanding of this phenomenon but leaves the diverse causal issues unexplored. Dietary calorie intake is modified by multiple social, economic, and cultural issues. Similarly, the reduction in energy expenditure in recent decades has complex origins, deriving from demographic and social change, which includes third-world transition from a labor-intensive agricultural economy to an industrial base, the introduction of household labor-saving devices, the popularity of transportation modes not reliant on physical effort, and from changed recreational habits, particularly in childhood (computer games instead of physical games). The prevalence of childhood obesity is escalating, having whimsically but not entirely unrealistically been attributed to “potato chips and computer chips.” Obesity and hypertension are intimately associated, and both very commonly coexist in individual patients with insulin resistance, hyperinsulinemia, and hyperlipidemia, this clustering of adverse health factors1 being designated the metabolic syndrome. The pathophysiological mechanisms by which obesity leads to hypertension remain uncertain. Understanding these processes might, perhaps, provide a more rational basis for drug treatment of obesity-related hypertension. Attempts at reduction in body weight, although pivotal in the treatment of obesity-related hypertension, more often than not fail, so that antihypertensive drug therapy is often needed. This review analyses the proposition that obesity is characterized by activation of the sympathetic nervous system and that obesity-related hypertension is, in fact, neurogenic, being initiated and sustained by neural mechanisms. At one time, this idea would have been held to fly in the …

Paradoxic Activation of the Renin-Angiotensin System in Twin-Twin Transfusion Syndrome: An Explanation for Cardiovascular Disturbances in the Recipient

Despite advances in treatment, twin-to-twin transfusion syndrome (TTTS) still carries a high risk for perinatal mortality and morbidity. Simple blood transfer from the donor to the recipient twin cannot explain all of the features of this disease, in particular the recipient's hypertensive cardiomyopathy. We report a case in which TTTS resulted in preterm delivery with early neonatal death of both twins, allowing assessment of the renin angiotensin system (RAS) status of each fetus, both by cord blood renin and aldosterone assay and by renal immunohistochemistry. The donor had severe oliguria/oligohydramnios, whereas the recipient, in addition to severe polyuria/polyhydramnios, had cardiomyopathy, atrioventricular regurgitation, and ascites. Although immunohistochemistry demonstrated that renal secretion of renin was up-regulated in the donor and down-regulated in the recipient, cord blood levels of renin and aldosterone were similar, with high renin levels in both twins. This observation supports the hypothesis that despite renal RAS down-regulation, the recipient is exposed to RAS effectors elaborated in the donor and transferred via placental shunts. This may contribute to cardiomyopathy and hypertension in the recipient, which cannot be accounted for by hypervolemia alone. We thus hypothesized that in TTTS, the recipient's hypertensive cardiomyopathy could be due to a mechanism similar to the classical model of hypertension referred to as "2 kidneys-1 clip." Thus the hypovolemic donor twin, comparable to the clipped kidney, produces vasoactive hormones that compromise the recipient, comparable to the normal kidney, causing hypertension and cardiomyopathy.

Cardiovascular and Renal Regulation by the Angiotensin Type 2 Receptor

The renin-angiotensin system is a coordinated hormonal cascade of major importance in cardiovascular and renal regulation. The principle effector of this system is the octapeptide angiotensin II (Ang II), which acts at 2 cell membrane receptors, AT1 and AT2. The majority of the actions of Ang II have been demonstrated to be mediated by the AT1 receptor, including growth promotion, vasoconstriction, antinatriuresis, aldosterone secretion, salt appetite, thirst, sympathetic outflow and inhibition of renin biosynthesis, and secretion.1 The AT2 receptor has been less well understood. Past studies, however, clearly demonstrated that the AT2 receptor mediates cellular differentiation and growth, opposing the actions of Ang II through the AT1 receptor.2 Studies in the mid to late 1990s demonstrated that AT2 receptor stimulation engenders an autacoid vasodilator cascade composed of bradykinin (BK), nitric oxide (NO), and guanosine cyclic 3′, 5′-monophosphate (cGMP).3–5 This discovery turned attention to the possibility that the AT2 receptor may mediate vasodilation, opposing the vasoconstrictor actions of Ang II at the AT1 receptor.6 Parallel cell signaling studies indicated that the AT2 receptor is G-protein–coupled (through Giα) and that receptor stimulation is accompanied by an increase in phosphotyrosine phosphatase activity and an inhibition of MAP kinase enzymes (p42 and p44) composing the extracellular signal-related kinase (ERK1/2). AT2 receptor-mediated inhibition of the extracellular signal-regulated kinase pathway opposed the actions of Ang II, resulting in extracellular signal-regulated kinase phosphorylation via the AT1 receptor.1,2,6,7 Work during the late 1990s through 2002 suggested that the AT2 receptor might serve as a vasodilator counterforce to the AT1 receptor.2,6,7 However, vasorelaxation was difficult to elicit in some experimental models, attributed to the relatively low level of AT2 receptor vascular expression compared with that of the …

Lectin chromatography of extrarenal renin protein in human plasma and tissues: Potential endocrine function via the renin receptor

Secretion of prorenin from extrarenal tissues comprises approximately half of the renin protein in plasma; its origin is unknown. The discovery of a prorenin/renin receptor that activates vascular tissue kinases raises interest in this otherwise inactive component. We have studied its glycosylation as this may distinguish it from renal renin. The binding of renin protein (active and prorenin) in human plasma and tissues to concanavalin (Con A) and wheat germ lectins was deployed. Immunoradiometric and enzyme kinetic assays were applied to column fractions. Mannosylated renin protein binds to Con A and has been shown to be taken up by human vascular and hepatic cells on mannose-6-phosphate receptors, possibly as a clearance mechanism. But the other binding sites of prorenin/renin that elicit a cellular phosphorylation response are apparently independent of glycosylation. The tissues examined (kidney, adrenal, ovary) each contain high proportions of Con A binding renin, but the plasma of normal resting males and females contain mainly non-binding renin, the proportion increasing as renal renin secretion decreases. The extreme of this relationship is seen in anephric patients and in some normal women on oral contraceptives with suppressed renal renin, in whom plasma renin is entirely non-binding to Con A. Conversely, when renal renin secretion was stimulated, the increased plasma active renin bound to Con A. However, extrarenal tissues containing exclusively Con A non-binding renin protein, and hence potential sources of anephric plasma renin protein, were not identified, but are unlikely to include adrenal or female reproductive tract. The findings are consistent with the view that normal human plasma contains a considerable amount of amannosylated prorenin of extrarenal origin that escapes hepatic clearance and has a longer half-life than renal renin. This plasma renin form would be expected to be activated in association with the recently described renin/prorenin aspartyl protease receptor and to participate in local pathophysiological processes.

Diuretic response to acute hypertension is blunted during angiotensin II clamp.

Acute hypertension inhibits proximal tubule (PT) fluid reabsorption. The resultant increase in end proximal flow rate provides the error signal to mediate tubuloglomerular feedback autoregulation of renal blood flow and glomerular filtration rate and suppresses renal renin secretion. To test whether the suppression of the renin-angiotensin system during acute hypertension affects the magnitude of the inhibition of PT fluid and sodium reabsorption, plasma ANG II levels were clamped by infusion of the angiotensin-converting enzyme (ACE) inhibitor captopril (12 microg/min) and ANG II after pretreatment with the bradykinin B(2) receptor blocker HOE-140 (100 microg/kg bolus). Because ACE also degrades bradykinin, HOE-140 was included to block effect of accumulating vasodilatory bradykinins during captopril infusion. HOE-140 increased the sensitivity of arterial blood pressure to ANG II: after captopril infusion without HOE-140, 20 ng x kg(-1) x min(-1) ANG II had no pressor effect, whereas with HOE-140, 20 ng x kg(-1) x min(-1) ANG II increased blood pressure from 104 +/- 4 to 140 +/- 6 mmHg. ANG II infused at 2 ng x kg(-1) x min(-1) had no pressor effect after captopril and HOE-140 infusion ("ANG II clamp"). When blood pressure was acutely increased 50-60 mmHg by arterial constriction without ANG II clamp, urine output and endogenous lithium clearance increased 4.0- and 6.7-fold, respectively. With ANG II clamp, the effects of acute hypertension were reduced 50%: urine output and endogenous lithium clearance increased two- and threefold, respectively. We conclude that HOE-140, an inhibitor of the B(2) receptor, potentiates the sensitivity of arterial pressure to ANG II and that clamping systemic ANG II levels during acute hypertension blunts the magnitude of the pressure diuretic response.

Rising behind NO: cGMP-dependent protein kinases.

Over the past few years, a wealth of biochemical and functional data has been gathered on mammalian cGMP-dependent protein kinases (cGKs). In mammals, three different kinases are encoded by two genes. Mutant and chimeric cGMP kinase proteins generated by molecular biology techniques have yielded important biochemical knowledge, such as the function of the N-terminal domains of cGKI and cGKII, the identity of the cGMP-binding sites of cGKI, the substrate specificity of the enzymes and structural details of the catalytic center. Genetic approaches have proved to be especially useful for the analysis of the biological function of cGKs. Recently, some of the in vivo targets and mechanisms leading to smooth muscle relaxation have been identified. In vivo targets are the myosin-binding subunit of myosin phosphatase (PP1M), a member of the protein phosphatase 1, the calcium-activated maxi K(+) channel and a new protein named IRAG that forms a complex with the inositol 1,4,5-trisphosphate (Ins(1,4,5)P(3)) receptor and cGKI. Phosphorylation of PP1M by cGKI(alpha) activates myosin phosphatase, whereas phosphorylation of IRAG by cGKI(beta) decreases Ins(1,4, 5)P(3)-induced calcium release. cGKII regulates in vivo intestinal fluid secretion by phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR), bone growth and renal renin secretion by phosphorylation of unknown proteins.