Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intraglomerular renin-angiotensin system enzyme activities have been examined previously using glomerular lysates and immune-based assays. However, preparation of glomerular extracts compromises the integrity of their anatomic architecture. In addition, antibody-based assays focus on angiotensin (Ang) II detection, ignoring the generation of other Ang I-derived metabolites, some of which may cross-react with Ang II. Therefore, our aim was to examine the metabolism of Ang I in freshly isolated intact glomeruli using matrix-assisted laser desorption ionization time of flight mass spectrometry as an analytic method. Glomeruli from male Sprague-Dawley rats were isolated by sieving and incubated in Krebs buffer in the presence of 1 micromol/L of Ang I for 15 to 90 minutes, with or without various peptidase inhibitors. Peptide sequences were confirmed by matrix-assisted laser desorption ionization time of flight tandem mass spectrometry or linear-trap-quadrupole mass spectrometry. Peaks were quantified using customized valine-(13)C(.15)N-labeled peptides as standards. The most prominent peaks resulting from Ang I cleavage were 899 and 1181 m/z, corresponding with Ang (1-7) and Ang (2-10), respectively. Smaller peaks for Ang II, Ang (1-9), and Ang (3-10) also were detected. The disappearance of Ang I was significantly reduced during inhibition of aminopeptidase A or neprilysin. In contrast, captopril did not alter Ang I degradation. Furthermore, during simultaneous inhibition of aminopeptidase A and neprilysin, the disappearance of Ang I was markedly attenuated compared with all of the other conditions. These results suggest that there is prominent intraglomerular conversion of Ang I to Ang (2-10) and Ang (1-7), mediated by aminopeptidase A and neprilysin, respectively. Formation of these alternative Ang peptides may be critical to counterbalance the local actions of Ang II. Enhancement of these enzymatic activities may constitute potential therapeutic targets for Ang II-mediated glomerular diseases.
Hypertension 2009 May
PMID:Angiotensin I is largely converted to angiotensin (1-7) and angiotensin (2-10) by isolated rat glomeruli. 1928 51

Hypertension affects 26% of adults and is in constant progress related to increased incidence of obesity and diabetes. One-third of hypertensive patients may be successfully treated with one antihypertensive agent, one-third may require two agents and in the remaining patients will need three agents for effective blood pressure (BP) control. The development of new classes of antihypertensive agents with different mechanisms of action therefore remains an important goal. Brain renin-angiotensin system (RAS) hyperactivity has been implicated in hypertension development and maintenance in several types of experimental and genetic hypertension animal models. Among the main bioactive peptides of the brain RAS, angiotensin (Ang) II and Ang III have similar affinities for type 1 (AT1) and type 2 (AT2) Ang II receptors. Following intracerebroventricular (i.c.v.) injection, Ang II and Ang III similarly increase arginine-vasopressin (AVP) release and BP. Blocking the brain RAS may be advantageous as it simultaneously (1) decreases sympathetic tone and consequently vascular resistance, (2) decreases AVP release, reducing blood volume and vascular resistance and (3) blocks angiotensin-induced baroreflex inhibition, decreasing both vascular resistance and cardiac output. However, as Ang II is converted to Ang III in vivo, the exact nature of the active peptide is not precisely determined. We summarize here the main findings identifying AngIII as one of the major effector peptides of the brain RAS in the control of AVP release and BP. Brain AngIII exerts a tonic stimulatory effect on BP in hypertensive rats, identifying brain aminopeptidase A (APA), the enzyme generating brain Ang III, as a potentially candidate target for hypertension treatment. This has led to the development of potent orally active APA inhibitors, such as RB150--the prototype of a new class of centrally acting antihypertensive agents.
 ...
PMID:The role of the brain renin-angiotensin system in hypertension: implications for new treatment. 2176 94

In angiotensin type 1 receptor-blocked rats, renal interstitial (RI) administration of des-aspartyl(1)-angiotensin II (Ang III) but not angiotensin II induces natriuresis via activation of angiotensin type 2 receptors. In the present study, renal function was documented during systemic angiotensin type 1 receptor blockade with candesartan in Sprague-Dawley rats receiving unilateral RI infusion of Ang III. Ang III increased urine sodium excretion, fractional sodium, and lithium excretion. RI coinfusion of specific angiotensin type 2 receptor antagonist PD-123319 abolished Ang III-induced natriuresis. The natriuretic response observed with RI Ang III was not reproducible with RI angiotensin (1-7) alone or together with angiotensin-converting enzyme inhibition. Similarly, neither RI angiotensin II alone or in the presence of aminopeptidase A inhibitor increased urine sodium excretion. In the absence of systemic angiotensin type 1 receptor blockade, Ang III alone did not increase urine sodium excretion, but natriuresis was enabled by the coinfusion of aminopeptidase N inhibitor and subsequently blocked by PD-123319. In angiotensin type 1 receptor-blocked rats, RI administration of aminopeptidase N inhibitor alone also induced natriuresis that was abolished by PD-123319. Ang III-induced natriuresis was accompanied by increased RI cGMP levels and was abolished by inhibition of soluble guanylyl cyclase. RI and renal tissue Ang III levels increased in response to Ang III infusion and were augmented by aminopeptidase N inhibition. These data demonstrate that endogenous intrarenal Ang III but not angiotensin II or angiotensin (1-7) induces natriuresis via activation of angiotensin type 2 receptors in the proximal tubule via a cGMP-dependent mechanism and suggest aminopeptidase N inhibition as a potential therapeutic target in hypertension.
Hypertension 2012 Aug
PMID:Intrarenal angiotensin III is the predominant agonist for proximal tubule angiotensin type 2 receptors. 2268 43

Brain renin-angiotensin system hyperactivity has been implicated in the development and maintenance of hypertension. We reported previously in the brain that aminopeptidase A and aminopeptidase N are involved in the metabolism of angiotensin II and angiotensin III, respectively. By using in vivo specific and selective aminopeptidase A and aminopeptidase N inhibitors, we showed that angiotensin III is one of the main effector peptides of the brain renin-angiotensin system, exerting a tonic stimulatory control more than blood pressure in hypertensive rats. Aminopeptidase A, the enzyme generating brain angiotensin III, thus represents a potential target for the treatment of hypertension. We demonstrated here the antihypertensive effects of RB150, a prodrug of the specific and selective aminopeptidase A inhibitor, EC33, in spontaneously hypertensive rats, a model of human essential hypertension. Oral administration of RB150 in conscious spontaneously hypertensive rats inhibited brain aminopeptidase A activity, demonstrating the central bioavailability of RB150 and its ability to generate EC33 into the brain. Oral RB150 treatment dose-dependently reduced blood pressure in spontaneously hypertensive rats with an ED(50) of 30 mg/kg, lasting for several hours. This decrease in blood pressure is partly attributed to a decrease in sympathetic tone, reducing vascular resistance. This treatment did not modify systemic renin-angiotensin system activity. Concomitant oral administration of RB150 with a systemic renin-angiotensin system blocker, enalapril, potentiated the RB150-induced blood pressure decrease achieved in <2 hours. Thus, RB150 may be the prototype of a new class of centrally active antihypertensive agents that might be used in combination with classic systemic renin-angiotensin system blockers to improve blood pressure control.
Hypertension 2012 Aug
PMID:Central antihypertensive effects of orally active aminopeptidase A inhibitors in spontaneously hypertensive rats. 2271 Jun 44

New insights into the intrarenal renin-angiotensin (Ang) system have modified our traditional view of the system. However, many finer details of this network of peptides and associated peptidases remain unclear. We hypothesized that a computational systems biology approach, applied to peptidomic data, could help to unravel the network of enzymatic conversions. We built and refined a Bayesian network model and a dynamic systems model starting from a skeleton created with established elements of the renin-Ang system and further developed it with archived matrix-assisted laser desorption ionization-time of flight mass spectra from experiments conducted in mouse podocytes exposed to exogenous Ang substrates. The model-building process suggested previously unrecognized steps, 3 of which were confirmed in vitro, including the conversion of Ang(2-10) to Ang(2-7) by neprilysin, Ang(1-9) to Ang(2-9), and Ang(1-7) to Ang(2-7) by aminopeptidase A. These data suggest a wider role of neprilysin and aminopeptidase A in glomerular formation of bioactive Ang peptides and shunting their formation. Other steps were also suggested by the model, and supporting evidence for those steps was evaluated using model-comparison methods. Our results demonstrate that systems biology methods applied to peptidomic data are effective in identifying novel steps in the Ang peptide processing network, and these findings improve our understanding of the glomerular renin-Ang system.
Hypertension 2013 Mar
PMID:Network modeling reveals steps in angiotensin peptide processing. 2328 55

The renin-angiotensin system is a coordinated hormonal cascade critical for the regulation of blood pressure (BP) and kidney function. Angiotensin (Ang) II, the major angiotensin effector peptide, binds to two major receptors, namely AT1 and AT2 receptors. The AT1 receptors engender antinatriuresis and raise BP, whereas AT2 receptors oppose these effects, inducing natriuresis and reducing BP. There is high AT2 receptor expression in the adult kidney, especially in the proximal tubule. In AT2 receptor-null mice, long-term AngII infusion results in pressor and antinatriuretic hypersensivivity compared with responses in wild-type mice. The major endogenous receptor ligand for AT2 receptor-mediated natriuretic responses appears to be des-aspartyl(1) -AngII (AngIII) instead of AngII. Recent studies have demonstrated that AngII requires metabolism to AngIII by aminopeptidase A to induce natriuresis and that inhibition of aminopeptidase N increases intrarenal AngIII and augments AngIII-induced natriuresis. The renal dopaminergic system is another important natriuretic pathway. Renal proximal tubule the D1 and D5 receptor subtypes (D1 -like receptors (D1LIKE R)) control approximately 50% of basal sodium excretion. Recently, we have found that natriuresis induced by proximal tubule D1LIKE R requires AT2 receptor activation and that D1LIKE R stimulation induces recruitment of AT2 receptors to the apical plasma membrane via a cAMP-dependent mechanism. Initial studies using the potent AT2 receptor non-peptide agonist Compound 21 demonstrate natriuresis in both the presence and absence of AT1 receptor blockade, indicating the therapeutic potential of this compound in fluid-retaining states and hypertension.
...
PMID:Role of angiotensin AT(2) receptors in natriuresis: Intrarenal mechanisms and therapeutic potential. 2333 17

The G protein-coupled receptor kinase 4 (GRK4) negatively regulates the dopaminergic system by desensitizing the dopamine-1-receptor. The expressional control of GRK4 has not been reported, but here we show that the transcription factor c-Myc binds to the promoter of GRK4 and positively regulates GRK4 protein expression in human renal proximal tubule cells (RPTCs). Addition of phorbol esters to RPTCs not only increased c-Myc binding to the GRK4 promoter but also increased both phospho-c-Myc and GRK4 expression. The phorbol ester-mediated increase in GRK4 expression was completely blocked by the c-Myc inhibitor, 10074-G5, indicating that GRK4 is downstream of phospho-c-Myc. The autocrine production of angiotensin II (Ang II) in RPTCs increased the phosphorylation and activation of c-Myc and subsequently GRK4 expression. 3-Amino-4-thio-butyl sulfonate, an inhibitor of aminopeptidase A, increased RPTC secretion of Ang II. 3-Amino-4-thio-butyl sulfonate or Ang II increased the expression of both phospho-c-Myc and GRK4, which was blocked by 10074-G5. Blockade of the Ang II type 1 receptor with losartan decreased phospho-c-Myc and GRK4 expression. Both inhibition of c-Myc activity and blockade of Ang II type 1 receptor restored the coupling of dopamine-1-receptor to adenylyl cyclase stimulation in uncoupled RPTCs, whereas phorbol esters or Ang II caused the uncoupling of normally coupled RPTCs. We suggest that the Ang II type 1 receptor impairs dopamine-1-receptor function via c-Myc activation of GRK4. This novel pathway may be involved in the increase in blood pressure in hypertension that is mediated by increased activity of the renin-angiotensin system and decreased activity of the renal dopaminergic system.
Hypertension 2013 May
PMID:A novel role for c-Myc in G protein-coupled receptor kinase 4 (GRK4) transcriptional regulation in human kidney proximal tubule cells. 2350 80

Hypertension is regulated through both the central and systemic renin-angiotensin systems. In the central renin-angiotensin system, zinc-dependent aminopeptidase A (APA) up-regulates blood pressure by specifically cleaving the N-terminal aspartate, but not the adjacent arginine, from angiotensin II, a process facilitated by calcium. Here, we determined the crystal structures of human APA and its complexes with different ligands and identified a calcium-binding site in the S1 pocket of APA. Without calcium, the S1 pocket can bind both acidic and basic residues through formation of salt bridges with the charged side chains. In the presence of calcium, the binding of acidic residues is enhanced as they ligate the cation, whereas the binding of basic residues is no longer favorable due to charge repulsion. Of the peptidomimetic inhibitors of APA, amastatin has higher potency than bestatin by fitting better in the S1 pocket and interacting additionally with the S3' subsite. These results explain the calcium-modulated substrate specificity of APA in central hypertension regulation and can guide the design and development of brain-targeting antihypertensive APA inhibitors.
...
PMID:Structural insights into central hypertension regulation by human aminopeptidase A. 2388 46

There is a persistent need for the development of new antihypertensive drugs, because the control of blood pressure is still not achievable in a significant proportion of hypertensive patients. Since the approval in 2007 of aliskiren, no other new antihypertensive based on new mechanism(s) of action have been approved. In fact, the development of promising novel drugs has been stopped for safety, efficacy or marketing reasons. Despite these difficulties, the pipeline is not dry and different new antihypertensive strategies targeting the renin-angiotensin-aldosterone pathway, are in clinical development stage. The dual angiotensin II receptor-neprilysin inhibitor LCZ696, a single molecule synthetized by cocrystallisation of valsartan and the neprilysin inhibitor prodrug AHU377 is in development for resistant hypertension and for heart failure. Daglutril is a dual neprylisin-endothelin converting enzyme inhibitor which was shown to decrease BP in patients with type 2 diabetic nephropathy. Aldosterone synthase inhibitors and the third and fourth generation non-steroidal dihydropyridine based mineralocorticoid receptors blockers are new ways to target the multiple noxious effects of aldosterone in the kidney, vessels and heart. Centrally acting aminopeptidase A inhibitors block brain angiotensin III formation, one of the main effector peptides of the brain renin angiotensin system. However, a long time will be still necessary to evaluate extensively the efficacy and safety of these new approaches. In the mean time, using appropriate and personalized daily doses of available drugs, decreasing physician inertia, improving treatment adherence, improving access to healthcare and reducing treatment costs remain major objectives to reduce the incidence of resistant hypertension.
...
PMID:New drug therapies interfering with the renin-angiotensin-aldosterone system for resistant hypertension. 2422 56

Hypertension affects one-third of the adult population and is a growing problem due to the increasing incidence of obesity and diabetes. Brain RAS (renin-angiotensin system) hyperactivity has been implicated in the development and maintenance of hypertension in several types of experimental and genetic hypertension animal models. We have identified in the brain RAS that APA (aminopeptidase A) and APN (aminopeptidase N), two membrane-bound zinc metalloproteases, are involved in the metabolism of AngII (angiotensin II) and AngIII (angiotensin III) respectively. The present review summarizes the main findings suggesting that AngIII plays a predominant role in the brain RAS in the control of BP (blood pressure). We first explored the organization of the APA active site by site-directed mutagenesis and molecular modelling. The development and the use in vivo of specific and selective APA and APN inhibitors EC33 and PC18 respectively, has allowed the demonstration that brain AngIII generated by APA is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over BP in conscious hypertensive rats. This identified brain APA as a potential therapeutic target for the treatment of hypertension, which has led to the development of potent orally active APA inhibitors, such as RB150. RB150 administered orally in hypertensive DOCA (deoxycorticosteroneacetate)-salt rats or SHRs (spontaneously hypertensive rats) crosses the intestinal, hepatic and blood-brain barriers, enters the brain, generates two active molecules of EC33 which inhibit brain APA activity, block the formation of brain AngIII and normalize BP for several hours. The decrease in BP involves two different mechanisms: a decrease in vasopressin release into the bloodstream, which in turn increases diuresis resulting in a blood volume reduction that participates in the decrease in BP and/or a decrease in sympathetic tone, decreasing vascular resistance. RB150 constitutes the prototype of a new class of centrally acting antihypertensive agents and is currently being evaluated in a Phase Ib clinical trial.
 ...
PMID:A new strategy for treating hypertension by blocking the activity of the brain renin-angiotensin system with aminopeptidase A inhibitors. 2469 96


<< Previous 1 2 3 4 5 6 Next >>