Renin and renin blockade have no role in complement activity.

Renin, an aspartate protease, regulates the renin-angiotensin system by cleaving its only known substrate angiotensinogen to angiotensin. Recent studies have suggested that renin may also cleave complement component C3 to activate complement or contribute to its dysregulation. Typically, C3 is cleaved by C3 convertase, a serine protease that uses the hydroxyl group of a serine residue as a nucleophile. Here, we provide seven lines of evidence to show that renin does not cleave C3. First, there is no association between renin plasma levels and C3 levels in patients with C3 Glomerulopathies (C3G) and atypical Hemolytic Uremic Syndrome (aHUS), implying that serum C3 consumption is not increased in the presence of high renin. Second, in vitro tests of C3 conversion to C3b do not detect differences when sera from patients with high renin levels are compared to sera from patients with normal/low renin levels. Third, aliskiren, a renin inhibitor, does not block abnormal complement activity introduced by nephritic factors in the fluid phase. Fourth, aliskiren does not block dysregulated complement activity on cell surfaces. Fifth, recombinant renin from different sources does not cleave C3 even after 24 hours of incubation at 37 °C. Sixth, direct spiking of recombinant renin into sera samples of patients with C3G and aHUS does not enhance complement activity in either the fluid phase or on cell surfaces. And seventh, molecular modeling and docking place C3 in the active site of renin in a position that is not consistent with a productive ground state complex for catalytic hydrolysis. Thus, our study does not support a role for renin in the activation of complement.

The interacting physiology of COVID-19 and the renin-angiotensin-aldosterone system: Key agents for treatment.

SARS-CoV-2 interacting with its receptor, angiotensin-converting enzyme 2 (ACE2), turns the host response to viral infection into a dysregulated uncontrolled inflammatory response. This is because ACE2 limits the production of the peptide angiotensin II (Ang II) and SARS-CoV-2, through the destruction of ACE2, allows the uncontrolled production of Ang II. Recovery from trauma requires activation of both a tissue response to injury and activation of a whole-body response to maintain tissue perfusion. Tissue and circulating renin-angiotensin systems (RASs) play an essential role in the host response to infection and injury because of the actions of Ang II, mediated via its AT1 receptor. Both tissue and circulating arms of the renin angiotensin aldosterone system's (RAAS) response to injury need to be regulated. The effects of Ang II and the steroid hormone, aldosterone, on fluid and electrolyte homeostasis and on the circulation are controlled by elaborate feedback networks that respond to alterations in the composition and volume of fluids within the circulatory system. The role of Ang II in the tissue response to injury is however, controlled mainly by its metabolism and conversion to Ang-(1-7) by the enzyme ACE2. Ang-(1-7) has effects that are contrary to Ang II-AT1 R mediated effects. Thus, destruction of ACE2 by SARS-CoV-2 results in loss of control of the pro-inflammatory actions of Ang II and tissue destruction. Therefore, it is the response of the host to SARS-CoV-2 that is responsible for the pathogenesis of COVID-19.

Antihypertensive activity of the ACE-renin inhibitory peptide derived from Moringa oleifera protein.

Moringa oleifera (MO) leaf is a potential plant protein resource with high nutritional and medicinal value. The study aims to investigate the hypotensive activity and stability of MO leaf peptides. MO leaf protein was extracted and then hydrolyzed with Alcalase to produce the MO leaf protein hydrolysate (MOPH). The MOPH was separated into peptide fractions with different molecular weights by membrane ultrafiltration. The MOPH and ultrafiltration fractions were evaluated for antihypertensive activity. Inhibition of the angiotensin-converting enzyme (84.71 ± 0.07%) and renin (43.72 ± 0.02%) was significantly higher for <1 kDa peptides when compared to other fractions. Oral administration of the <1 kDa component in spontaneously hypertensive rats positively lowers the blood pressure (∼17 mmHg). The <1 kDa component was isolated and purified subsequently; the final active component was identified by mass spectrometry and amino acid sequence analysis. Two highly active ACE (angiotensin-converting enzyme) and renin dual inhibitory peptides Leu-Gly-Phe-Phe (LGF) and Gly-Leu-Phe-Phe (GLFF) were obtained. The two peptides exhibited a good dual inhibitory activity of ACE and renin with IC50 values of LGF (0.29 ± 0.13 mM, 1.88 ± 0.08 mM) and GLFF (0.31 ± 0.04 mM, 2.80 ± 0.08 mM). Furthermore, in vivo models, LGF and GLFF significantly reduced the systolic blood pressure (19.4 mmHg; 18.2 mmHg) and diastolic blood pressure (12 mmHg; 13.8 mmHg) of SHRs (spontaneously hypertensive rats). The peptide transmembrane transport experiments and simulated gastrointestinal digestion experiments with LGF and GLFF showed that they can resist gastrointestinal digestion in a complete form. Thus, bioactive peptides from MO leaf may possess the potential to be used for treating hypertension in humans.

The effect of neprilysin and renin inhibition on the renal dysfunction following ischemia-reperfusion injury in the rat.

The natriuretic peptide (NP) system counter-regulates the renin-angiotensin system (RAS), so enhancing the activity of natriuretic peptides (NPs) may be beneficial in conditions when RAS is activated such as ischemia-reperfusion injury (IRI). Neprilysin is the key enzyme responsible for the degradation of NPs. The effects of neprilysin inhibition or the combination of neprilysin inhibition and RAS inhibition on renal IRI-induced renal dysfunction have not been investigated yet. To investigate this, rats underwent sham surgery or bilateral IRI for 20 min. G-Als, G-Scb, and G-Als+Scb underwent similar protocol but received aliskiren (renin inhibitor), sacubitril (neprilysin inhibitor) or a combination of both pre- and post-IRI, respectively. IRI caused significant alterations in all renal functional parameters, markers of acute renal injury, pro-inflammatory and pro-fibrotic cytokines, and histological features. All these alterations were significantly attenuated in G-Als, G-Scb, and G-Als+Scb. The attenuations in the alterations in serum creatinine, creatinine clearance, and histological features were larger in G-Als+Scb compared to either G-Als or G-Scb. We conclude that RAS blockade by a renin inhibitor (aliskiren) or neprilysin inhibition by sacubitril separately led to significant attenuation in the renal IRI-induced renal dysfunction. The combination of aliskiren and sacubitril was more effective than either one alone.

Ambulatory Treatments for RAAS Inhibitor-Related Hyperkalemia and the 1-Year Risk of Recurrence.

BACKGROUND AND OBJECTIVE: The optimal ambulatory management of renin-angiotensin-aldosterone system inhibitor (RAASi)-related hyperkalemia to reduce the risk of recurrence is unknown. We examined the risk of hyperkalemia recurrence on the basis of outpatient pharmacologic changes following an episode of RAASi-related hyperkalemia. DESIGN: We performed a population-based, retrospective cohort study of older adults (n=49,571; mean age 79 years) who developed hyperkalemia (potassium ≥5.3 mEq/L) while on a RAASi and were grouped as follows: no intervention, RAASi discontinuation, RAASi dose decrease, new diuretic, diuretic dose increase, or sodium polystyrene sulfonate within 30 days. The primary outcome was hyperkalemia recurrence, with secondary outcomes of cardiovascular events and all-cause mortality within 1 year. RESULTS: Among patients who received a pharmacologic intervention (23% of the cohort), RAASi discontinuation was the most commonly prescribed strategy (74%), followed by RAASi decrease (15%), diuretic increase (7%), new diuretic (3%), and sodium polystyrene sulfonate (1%). A total of 16,977 (34%) recurrent hyperkalemia events occurred within 1 year. Compared with no intervention (35%, referent), the cumulative incidence of recurrent hyperkalemia was lower with RAASi discontinuation (29%; hazard ratio, 0.82; 95% confidence interval, 0.78 to 0.85), whereas there was no difference with RAASi dose decrease (36%; hazard ratio, 0.94; 95% confidence interval, 0.86 to 1.02), new diuretic (32%; hazard ratio, 0.95; 95% confidence interval, 0.78 to 1.17), or diuretic increase (38%; hazard ratio, 0.99; 95% confidence interval, 0.87 to 1.12) and a higher incidence with sodium polystyrene sulfonate (55%; hazard ratio, 1.30; 95% confidence interval, 1.04 to 1.63). RAASi discontinuation was not associated with a higher risk of 1-year cardiovascular events (hazard ratio, 0.96; 95% confidence interval, 0.91 to 1.02) or all-cause mortality (hazard ratio, 1.05; 95% confidence interval, 0.96 to 1.15) compared with no intervention. CONCLUSIONS: Among older adults with RAASi-related hyperkalemia, RAASi discontinuation is associated with the lowest risk of recurrent hyperkalemia, with no apparent increase in short-term risks for cardiovascular events or all-cause mortality.

Functional and molecular evaluation of using aliskiren during acute and chronic partial ureteral obstruction in rat solitary kidney.

AIMS: To study the effect of direct renin inhibitor (aliskiren) on the renal function during acute and chronic partial ureteral obstruction (PUO) in rat solitary kidney. MAIN METHODS: Sixty male Sprague-Dawley rats were randomly allocated into three groups (20 rats each); sham, PUO and aliskiren groups. Right nephrectomy was performed in all groups. Rats in PUO and aliskiren groups were subjected to left PUO and received no treatment and aliskiren (10 mg/kg, orally, once per day till sacrification), respectively. Blood samples were then collected for biochemical measurements. Ten rats from each group were sacrificed after two weeks, while the remaining rats were sacrificed after four weeks. Left kidneys were harvested for histopathological examination, BCL-2, interleukin (IL)-6, transforming growth factor (TGF)-ß1, collagen I and fibronectin relative gene expression and assessment of glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) activity. KEY FINDINGS: After two and four weeks of PUO, aliskiren significantly recompensed the rise of serum creatinine (Scr) and blood urea nitrogen (BUN). Aliskiren also revealed significantly better histopathological results regarding cortical and medullary necrosis, regeneration and inflammatory cell infiltration. Aliskiren group showed statistically significant up-regulation of BCL-2 and down-regulation of IL-6, TGF-ß1, collagen I and fibronectin relative gene expression. Aliskiren significantly increased GSH and SOD activity and reduced MDA and NO activity. Moreover, aliskiren administration for four weeks after PUO significantly yielded more renoprotective effect compared to its administration for two weeks. SIGNIFICANCE: Aliskiren ameliorates the deterioration of the renal function during acute and chronic PUO in a solitary kidney.

Repurposing of renin inhibitors as SARS-COV-2 main protease inhibitors: A computational study.

The COVID-19 pandemic has urged for the repurposing of existing drugs for rapid management and treatment. Renin inhibitors down regulation of ACE2, which is an essential receptor for SARS-CoV-2 infection that is responsible for COVID-19, in addition to their ability to act as protease inhibitors were encouraging aspects for their investigation as possible inhibitors of main protease of SARS-CoV-2 via computational studies. A Pharmacophore model was generated using the newly released SARS-COV-2 main protease inhibitors. Virtual screening was performed on renin inhibitors, and Drug likeness filter identified remikiren and 0IU as hits. Molecular docking for both compounds showed that the orally active renin inhibitor remikiren (Ro 42-5892) of Hoffmann-La Roche exhibited good molecular interaction with Cys145 and His41 in the catalytic site of SARS-CoV-2 main protease. Molecular dynamics simulation suggested that the drug is stable in the active site of the enzyme.

Modeling the Molecular Impact of SARS-CoV-2 Infection on the Renin-Angiotensin System.

SARS-CoV-2 infection is mediated by the binding of its spike protein to the angiotensin-converting enzyme 2 (ACE2), which plays a pivotal role in the renin-angiotensin system (RAS). The study of RAS dysregulation due to SARS-CoV-2 infection is fundamentally important for a better understanding of the pathogenic mechanisms and risk factors associated with COVID-19 coronavirus disease and to design effective therapeutic strategies. In this context, we developed a mathematical model of RAS based on data regarding protein and peptide concentrations; the model was tested on clinical data from healthy normotensive and hypertensive individuals. We used our model to analyze the impact of SARS-CoV-2 infection on RAS, which we modeled through a downregulation of ACE2 as a function of viral load. We also used it to predict the effect of RAS-targeting drugs, such as RAS-blockers, human recombinant ACE2, and angiotensin 1-7 peptide, on COVID-19 patients; the model predicted an improvement of the clinical outcome for some drugs and a worsening for others. Our model and its predictions constitute a valuable framework for in silico testing of hypotheses about the COVID-19 pathogenic mechanisms and the effect of drugs aiming to restore RAS functionality.

Ramipril blunts glycerol-induced acute renal failure in rats through its antiapoptosis, anti-inflammatory, antioxidant, and renin-inhibiting properties.

OBJECTIVES: Acute kidney injury (AKI) is a malady with a sudden onset resulting in buildup of waste matters in the body, but a specific cure hasn't been found as a lasting solution to AKI. In this study, ramipril was evaluated for its potential therapy in glycerol-induced AKI in rats. METHODS: Twenty animals were divided into four groups of five animals each. Group I was the control while group II was given glycerol on day 8 only, groups III and IV were administered with pioglitazone (reference drug) and ramipril for seven days respectively and on day 8 received glycerol. On the ninth day, blood and tissue samples were taken to assay for serum indicators of oxidative damage, enzymatic and nonenzymatic antioxidants, and creatinine and blood urea nitrogen. Animals were sacrificed thereafter; kidney was harvested for histological and immunohistochemical analysis. Expressions of caspase 3, renin receptor, NK-KB, and KIM-1 were carried out. RESULTS: Ramipril significantly inhibited indicators of oxidative damage while also significantly increasing levels of enzymatic and nonenzymatic antioxidant markers. These drugs also significantly lowered the levels of creatinine and blood urea nitrogen. Histology also indicated that while there were massive infiltration of leucocytes and congestion of the kidney in toxicant group, the ramipril-treated group showed a milder condition. In immunohistochemistry, the two drugs significantly inhibited the expressions of the four proteins, which were highly expressed in the toxicant group. CONCLUSIONS: The study showed that ramipril and pioglitazone have nephroprotective effect and thus have the ability to blunt AKI through their anti-inflammatory, antiapoptosis, antirenin, and antioxidant properties.

Angiotensin dependent and angiotensin independent protective effects of renin-b in H9c2 cells after anoxia.

The renin-angiotensin system is known to regulate blood pressure as well as water- and electrolyte balance. An activated RAS is involved in the development of hypertension and hypertension-related organ damage. Thus, inhibitors of the RAS are protective and markedly increasing the life span of patients. In contrast, renin transcripts have been discovered encoding a cytoplasmatic renin isoform, termed renin-b, which is not harmful but may be even protective. Here we demonstrate that depletion of renin-b encoding transcripts by small interference RNA decreased ATP levels and increased basal necrosis as well as apoptosis rates. Furthermore, renin-b depletion potentiated the anoxia-induced increase of necrosis rates. Vice versa, overexpression of renin-b prevented the anoxia-induced increase of caspase-mediated apoptosis rates. Besides, cells overexpressing renin-b exhibited even reduced mitochondrial mediated apoptosis rates under anoxia, when compared with normoxic conditions, as indicated by Annexin V labeling. However, whereas the protective effect of renin-b on caspase-mediated apoptosis was completely blocked by the renin inhibitor CH732, the effect on mitochondrial-mediated apoptosis was not affected by CH732 at all. From these data we conclude that renin-b overexpression mediates cardioprotective effects under anoxia with respect to mitochondrial induced apoptosis angiotensin-independently, but with respect to caspase induced apoptosis likely in an angiotensin-dependent manner.

Renin inhibitors versus angiotensin converting enzyme (ACE) inhibitors for primary hypertension.

BACKGROUND: Renin inhibitors (RIs) reduce blood pressure more than placebo, with the magnitude of this effect thought to be similar to that for angiotensin converting enzyme (ACE) inhibitors. However, a drug's efficacy in lowering blood pressure cannot be considered as a definitive indicator of its effectiveness in reducing mortality and morbidity. The effectiveness and safety of RIs compared to ACE inhibitors in treating hypertension is unknown. OBJECTIVES: To evaluate the benefits and harms of renin inhibitors compared to ACE inhibitors in people with primary hypertension. SEARCH METHODS: The Cochrane Hypertension Group Information Specialist searched the following databases for randomized controlled trials up to August 2020: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers about further published and unpublished work. The searches had no language restrictions. SELECTION CRITERIA: We included randomized, active-controlled, double-blinded studies (RCTs) with at least four weeks follow-up in people with primary hypertension, which compared renin inhibitors with ACE inhibitors and reported morbidity, mortality, adverse events or blood pressure outcomes. We excluded people with proven secondary hypertension. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the included trials, evaluated the risks of bias and entered the data for analysis. MAIN RESULTS: We include 11 RCTs involving 13,627 participants, with a mean baseline age from 51.5 to 74.2 years. Follow-up duration ranged from four weeks to 36.6 months. There was no difference between RIs and ACE inhibitors for the outcomes: all-cause mortality: risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.18; 5 RCTs, 5962 participants; low-certainty evidence; total myocardial infarction: RR 0.86, 95% CI 0.22 to 3.39; 2 RCTs, 957 participants; very low-certainty evidence; adverse events: RR 0.98, 95% CI 0.93 to 1.03; 10 RTCs, 6007 participants;  moderate-certainty evidence; serious adverse events: RR 1.21, 95% CI 0.89 to 1.64; 10 RTCs, 6007 participants; low-certainty evidence; and withdrawal due to adverse effects: RR 0.85, 95% CI 0.68 to 1.06; 10 RTCs, 6008 participants; low-certainty evidence. No data were available for total cardiovascular events, heart failure, stroke, end-stage renal disease or change in heart rate. Low-certainty evidence suggested that RIs reduced systolic blood pressure: mean difference (MD) -1.72, 95% CI -2.47 to -0.97; 9 RCTs, 5001 participants;  and diastolic blood pressure: MD -1.18, 95% CI -1.65 to -0.72; 9 RCTs, 5001 participants,  to a greater extent than ACE inhibitors, but we judged this to be more likely due to bias than a true effect.  AUTHORS' CONCLUSIONS: For the treatment of hypertension, we have low certainty that renin inhibitors (RI) and angiotensin converting enzyme (ACE) inhibitors do not differ for all-cause mortality and myocardial infarction. We have low to moderate certainty that they do not differ for adverse events. Small reductions in blood pressure with renin inhibitors compared to ACE inhibitors are of low certainty.  More independent, large, long-term trials are needed to compare RIs with ACE inhibitors, particularly assessing morbidity and mortality outcomes, but also on blood pressure-lowering effect.

In vitro anti-hypertensive activity of Jasminum grandiflorum subsp. floribundum (Oleaceae) in relation to its metabolite profile as revealed via UPLC-HRMS analysis.

Jasminum is an important genus in the olive family (Oleaceae), comprising about 200 species distributed all over the world. In the current study, the methanolic extract of Jasminum grandiflorum subsp. floribundum aerial parts and its respective fractions; dichloromethane and n-butanol fractions were analyzed using ultra-performance liquid chromatography coupled to high resolution mass (UPLC-HRMS) for profiling and characterization of the plant metabolites. More than seventy metabolites were identified belonging to different classes including phenolic acids, flavonoids, secoiridoids, iridoids, lignans, fatty acids, and triterpenes. The samples were also assessed for their angiotensin-I-converting enzyme (ACE) and renin inhibitory activity along with their antioxidant potential using five complementary assays: TAC (total antioxidant capacity), DPPH (1,1-diphenyl-2-picrylhydrazyl), ABTS (2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid), FRAP (ferric reducing antioxidant power) and iron reducing power. The results revealed that the n-butanol fraction showed a potent ACE and renin inhibition as compared to Lisinopril and Aliskiren standard drugs (24.66 ± 2.41 ng/mL vs. 18.37 ± 1.21 ng/mL and 141.14 ± 5.28 ng/mL vs. 447.87 ± 3.2 ng/mL, respectively) and also a strong antioxidant activity. Interestingly, the secoiridoids, dominated metabolites detected in the n-butanol fraction, revealed the potential of them for management of the hypertension diseases. The total extract and fractions were also standardized using HPLC analysis of the major secoiridoid glycoside; oleuropein. Finally, J. grandiflorum standardized extract could be considered as a target for further studies to discover a new therapeutic anti-hypertensive drug.

Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study.

BACKGROUND: Concerns have been raised about the possibility that inhibitors of the renin-angiotensin-aldosterone system (RAAS) could predispose individuals to severe COVID-19; however, epidemiological evidence is lacking. We report the results of a case-population study done in Madrid, Spain, since the outbreak of COVID-19. METHODS: In this case-population study, we consecutively selected patients aged 18 years or older with a PCR-confirmed diagnosis of COVID-19 requiring admission to hospital from seven hospitals in Madrid, who had been admitted between March 1 and March 24, 2020. As a reference group, we randomly sampled ten patients per case, individually matched for age, sex, region (ie, Madrid), and date of admission to hospital (month and day; index date), from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish primary health-care database, in its last available year (2018). We extracted information on comorbidities and prescriptions up to the month before index date (ie, current use) from electronic clinical records of both cases and controls. The outcome of interest was admission to hospital of patients with COVID-19. To minimise confounding by indication, the main analysis focused on assessing the association between COVID-19 requiring admission to hospital and use of RAAS inhibitors compared with use of other antihypertensive drugs. We calculated odds ratios (ORs) and 95% CIs, adjusted for age, sex, and cardiovascular comorbidities and risk factors, using conditional logistic regression. The protocol of the study was registered in the EU electronic Register of Post-Authorisation Studies, EUPAS34437. FINDINGS: We collected data for 1139 cases and 11 390 population controls. Among cases, 444 (39·0%) were female and the mean age was 69·1 years (SD 15·4), and despite being matched on sex and age, a significantly higher proportion of cases had pre-existing cardiovascular disease (OR 1·98, 95% CI 1·62-2·41) and risk factors (1·46, 1·23-1·73) than did controls. Compared with users of other antihypertensive drugs, users of RAAS inhibitors had an adjusted OR for COVID-19 requiring admission to hospital of 0·94 (95% CI 0·77-1·15). No increased risk was observed with either angiotensin-converting enzyme inhibitors (adjusted OR 0·80, 0·64-1·00) or angiotensin-receptor blockers (1·10, 0·88-1·37). Sex, age, and background cardiovascular risk did not modify the adjusted OR between use of RAAS inhibitors and COVID-19 requiring admission to hospital, whereas a decreased risk of COVID-19 requiring admission to hospital was found among patients with diabetes who were users of RAAS inhibitors (adjusted OR 0·53, 95% CI 0·34-0·80). The adjusted ORs were similar across severity degrees of COVID-19. INTERPRETATION: RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19. FUNDING: Instituto de Salud Carlos III.

Clinical efficacy, safety and tolerability of Aliskiren Monotherapy (AM): an umbrella review of systematic reviews.

BACKGROUND: Aliskiren is a newly developed drug. Its role in lowering BP has been recognized. However, the role of aliskiren in treating heart and renal diseases are still controversial. OBJECTIVE: To evaluate the existing evidence about clinical efficacy, safety and tolerability of aliskiren monotherapy (AM). METHODS: An umbrella review of systematic reviews of interventional studies. We searched Pubmed, Embase and Cochrane Library up to June 2019. Two reviewers applied inclusion criteria to the select potential articles independently. The extract and analyze of accessible data were did by two reviewers independently too. Discrepancies were resolved with discussion or the arbitration of the third author. RESULTS: Eventually, our review identified 14 eligible studies. Results showed that for essential hypertension patients, aliskiren showed a great superiority over placebo in BP reduction, BP response rate and BP control rate. Aliskiren and placebo, ARBs or ACEIs showed no difference in the number or extent of adverse events. For heart failure patients, AM did not reduce BNP levels (SMD -0.08, - 0.31 to 0.15) or mortality rate (RR 0.76, 0.32 to 1.80), but it decreased NT-proBNP (SMD -0.12, - 0.21 to - 0.03) and PRA levels (SMD 0.52, 0.30 to 0.75), increased PRC levels (SMD -0.66, - 0.8 to - 0.44). For patients who are suffered from hypertension and diabetes and/or nephropathy or albuminuria at the same time, aliskiren produced no significant effects (RR 0.97, 0.81 to 1.16). CONCLUSION: We found solid evidence to support the benefits of aliskiren in the treatment of essential hypertension, aliskiren can produce significant effects in lowering BP and reliable safety. However, the effects of aliskiren in cardiovascular and renal outcomes were insignificant. TRIAL REGISTRATION: Study has been registered in PROSPERO (CRD42019142141).

RAS inhibition modulates kynurenine levels in a CKD population with and without type 2 diabetes mellitus.

Kynurenine pathway of tryptophan metabolism is involved in the pathophysiology of chronic kidney disease (CKD) and diabetes mellitus, mainly through the inflammation-induced activity of indoleamine 2,3-dioxygenase (IDO), and few studies have investigated its potential link with proteinuria. Renin-angiotensin system inhibitors (RASis) are recommended in these patients to decrease proteinuria, slow CKD progression and reduce cardiovascular risk, but whether these drugs influence kynurenine levels in humans is unknown. We evaluated serum tryptophan and kynurenine in patients suffering from CKD with or without type 2 diabetes mellitus, their correlations with markers of reduced kidney function, and their relationship with RAS-inhibiting therapy. Of 72 adult patients enrolled, 55 were receiving RASis, whereas 17 were not. Tryptophan was assessed by HPLC (high-performance liquid chromatography); kynurenine was measured using an enzyme-linked immunosorbent assay kit; IDO activity (%) was calculated with the formula (kynurenine/tryptophan) × 100. Kynurenine levels were significantly lower in the group under RASis compared to the untreated group (1.56 ± 0.79 vs 2.16 ± 1.51 µmol/l; P = 0.0378). In patients not receiving RASis, kynurenine was inversely related to estimated glomerular filtration rate (eGFR) (r = - 0.4862; P = 0.0478) and directly related to both proteinuria (ρ = 0.493; P = 0.0444) and albuminuria (ρ = 0.542; P = 0.0247). IDO activity was higher in patients with history of cardiovascular disease compared to patients with no such history, and it negatively correlated with eGFR (ρ = - 0.554; P = 0.0210) in the same group. These findings may contribute to explain the well-known beneficial effects of RAS inhibition in CKD population, especially considering that kynurenine is emerging as a potential new biomarker of CKD.

[Preliminary clinical analysis of direct renin inhibitor aliskiren in the treatment of severe coronavirus disease 2019 patients with hypertension].

Objective: To explore the feasibility of direct renin inhibitor aliskiren for the treatment of severe or critical coronavirus disease 2019 (COVID-19) patients with hypertension. Methods: The antihypertensive effects and safety of aliskiren was retrospectively analyzed in three severe and one critical COVID-19 patients with hypertension. Results: Four patients, two males and two females, with an average age of 78 years (66-87 years), were referred to hospital mainly because of respiratory symptoms. Three were diagnosed by positive novel coronavirus 2019 (2019-nCoV) nucleic acid or antibody, and the critical patient with cardiac insufficiency was clinically determined. Two patients were treated with calcium channel antagonist (CCB), one with angiotensin converting enzyme inhibitor (ACEI), and one with angiotensin Ⅱ receptor antagonist (ARB). After admission, ACEI and ARB were discontinued, one patient with heart failure was treated by aliskiren combined with diuretic.Three patients were treated with aliskiren combined with CCB among whom two withdrew CCB due to low blood pressure after 1 to 2 weeks. Based on comprehensive treatment including antiviral and oxygenation treatment, blood pressure was satisfactorily controlled by aliskiren after three to four weeks without serious adverse events. All patients were finally discharged. Conclusion: Our preliminary clinical data shows that antihypertensive effect of aliskiren is satisfactory and safe for severe COVID-19 patients complicated with hypertension.

Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules.

Hypertension is a diverse illness interlinked with cerebral, cardiovascular (CVS) and renal abnormalities. Presently, the malady is being treated by focusing on Renin- angiotensin system (RAS), voltage-gated calcium channels, peripheral vasodilators, renal and sympathetic nervous systems. Cardiovascular and renal abnormalities are associated with the overactivation of RAS, which can be constrained by angiotensin- converting enzyme inhibitors (ACEIs), angiotensin II (Ang-II) -AT1 receptor blockers (ARBs) and renin inhibitors. The latter is a new player in the old system. The renin catalyzes the conversion of angiotensinogen to Angiotensin I (Ang-I). This can be overcome by inhibiting renin, a preliminary step, eventually hinders the occurrence of the cascade of events in the RAS. Various peptidomimetics, the first-generation renin inhibitors developed six decades ago have limited drug-like properties as they suffered from poor intestinal absorption, high liver first-pass metabolism and low oral bioavailability. The development of chemically diverse molecules from peptides to nonpeptides expanded the horizon to achieving direct renin inhibition. Aliskiren, a blockbuster drug that emerged as a clinical candidate and got approved by the US FDA in 2007 was developed by molecular modeling studies. Aliskiren indicated superior to average efficacy and with minor adverse effects relative to other RAS inhibitors. However, its therapeutic use is limited by poor oral bioavailability of less than 2% that is similar to first-generation peptidic compounds. In this review, we present the development of direct renin inhibitors (DRIs) from peptidic to nonpeptidics that lead to the birth of aliskiren, its place in the treatment of cardiovascular diseases and its limitations.

Add-on aliskiren treatment can decrease blood pressure but requires attention to risks of renal impairment and hyperkalemia Chikushi Anti-Hypertension Trial-Rasilez® (CHAT-Ras).

BACKGROUND: Renin is the starting point of the renin angiotensin (RA) system cycle. Aliskiren (AL), which is a direct renin inhibitor, suppressed the entire RA cycle. In the present study, the efficacy of add-on of AL treatment in patients with essential hypertension (HT) was investigated. METHODS: This study was a multi-center, open-label, prospective, observational study. Study subjects were patients with essential HT and poor blood pressure (BP) control, who had received calcium channel blocker monotherapy or angiotensin II receptor blocker monotherapy or had not received any BP lowering drugs. Following add-on of AL for 12 months, BP and additional laboratory findings were analyzed. RESULTS: A total of 150 subjects were enrolled. There were 50 dropout subjects including discontinuation. Dropouts were the highest in the ARB combination therapy group at 9 subjects due to adverse events, and 3 of them were due to hyperkalemia. A significantly higher number of patients with chronic kidney disease (CKD) dropped out compared to patients without CKD (φ = 0.166, p < .05). BP before add-on of AL was 155/88 mmHg. After add-on of AL, BP was significantly improved and this lowering was sustained for 3 months (136/78 mmHg, p < .001), 6 months (136/77 mmHg, p < .001) and 12 months (134/78 mmHg, p < .001). In contrast, add-on of AL increased the potassium level and decreased the estimated glomerular filtration rate. CONCLUSION: While add-on AL treatment achieved a favorable and sustained decrease of BP in this study, caution is necessary with regard to elevation of potassium levels and renal impairment.

The Nonclinical Pharmacokinetics and Prediction of Human Pharmacokinetics of SPH3127, a Novel Direct Renin Inhibitor.

BACKGROUND: SPH3127 is a novel direct renin inhibitor designed as an oral drug for the regulation of blood pressure and body fluid homeostasis via the renin-angiotensin-aldosterone system (RAAS). This candidate is now being evaluated in a phase I clinical trial in China. OBJECTIVES: The purpose of this study is to investigate detailed nonclinical pharmacokinetic data, and to predict human pharmacokinetic parameters. METHODS: In vivo pharmacokinetic studies of SPH3127 were performed to investigate the exposure, absorption, clearance, distribution and metabolism after intravenous and oral administration in rats, beagle dogs and cynomolgus monkeys. The cynomolgus monkey pharmacokinetics/pharmacodynamics study was conducted to investigate the effect-concentration relationship of SPH3127. Its human pharmacokinetic properties were predicted employing an allometric scaling approach based on non-clinical species data. In vitro studies were also employed in a cytochrome P450 (CYP) enzyme phenotyping study, an inhibition and induction study, and a Caco-2 cell permeation and metabolites profile analysis. RESULTS: After a single intravenous administration of SPH3127 in rats and monkeys, high clearance and volume of distribution and a short terminal elimination half-life were seen for both species. The oral bioavailability of SPH3127 to rats and monkeys was about 11.5-24.5% and 3.3-11.3%, respectively, with the short peak time, Tmax, ranging from 0.25 to 1.3 h. SPH3127 shows low permeability across Caco-2 cell membranes, and as the substrate of p-gp with apparent efflux characteristics. SPH3127 is mainly distributed in the gastrointestine, liver, kidney, pancreas and lung after oral dose in rats, and which decreased quickly to a 1% peak concentration during 12 h. The plasma protein binding ratio of SPH3127 is low as 11.7-14.8% for all species. Excretion studies in rats suggested that fecal, urine and bile excretion represented about 15% of the intake dose, indicating that SPH3127 undergoes extensive metabolism after oral dosing. Phenotyping data revealed that CYP3A4 was the most active enzyme catalyzing the metabolism of SPH3127. The key metabolites were likely N-hydroxylation (M8-7), mono-oxidation-dehydrogenation (M7-4) and mono-oxidation (M8-1, M8-2), both for in vitro liver microsome incubation of all species and in vivo results in rats. The in vitro CYP inhibition study only found very weak action for CYP3A4 (midazolam 1'-hydroxylation) and CYP3A4 (midazolam 6ß-hydroxylation) with IC50 of 56.8 µM and 41.1 µM, respectively. Monkey pharmacokinetic/pharmacodynamic data showed favorable safety margins when compared with the exposure of the effect dose and that of the monkey NOAEL level. Simple four-species allometric scaling led to predicted human plasma clearance and volume of distribution, and then simulated the oral human plasma concentration-time profile, which are both in good consistency with phase I clinical trial pharmacokinetic data. CONCLUSIONS: SPH 3127 has appropriate pharmacokinetic properties for further clinical exploration.