Renin as a Prognostic Marker in Intensive Care and Perioperative Settings: A Scoping Review.

Serum renin increases in response to sympathetic nerve activation and hypotension. Recent studies have reported the association of serum renin levels with adverse clinical outcomes in acute care settings. This scoping review aimed to systematically review the available literature on renin as a prognostic marker in intensive care and perioperative patients. We searched for studies published since inception until March 31, 2023, which assessed the association between serum renin levels and clinical outcomes or the effect of synthetic angiotensin II administration on serum renin levels in critically ill and perioperative patients in PubMed, Embase, and the Cochrane Library. The primary outcome was mortality at the longest follow-up; the secondary outcomes were adverse renal outcomes (ie, acute kidney injury, the need for renal replacement therapy, and major adverse kidney events), hemodynamic instability, outcomes to angiotensin II administration, and prognostic performance for mortality when compared with lactate. Among the 2081 studies identified, we included 16 studies with 1573 patients (7 studies on shock, 5 on nonspecific critical illness, 2 on cardiac surgery, 1 on noncardiac surgery, and 1 on coronavirus disease 2019). A significant association between serum renin levels and poor outcomes was identified in 14 studies, with 10 studies demonstrating an association with mortality. One post hoc analysis found that angiotensin II administration reduced mortality in patients with markedly elevated renin values. Two studies showed that renin was superior to lactate as a prognostic marker of mortality. Our scoping review showed that elevated serum renin levels may be associated with clinically relevant outcomes among various perioperative and intensive care populations. Increased serum renin levels may identify patients in which synthetic angiotensin II administration improves clinical outcomes and may outperform serum lactate in predicting mortality.

A low dose of daily licorice intake affects renin, aldosterone, and home blood pressure in a randomized crossover trial.

BACKGROUND: Licorice, through the effects of glycyrrhizic acid (GA), raises blood pressure (BP). The World Health Organization has suggested that 100 mg GA/d would be unlikely to cause adverse effects, but of 13 previously published studies none have been randomized and controlled and independently quantified the GA content. OBJECTIVE: Our aim was to analyze the effects on home BP of a daily licorice intake containing 100 mg GA. METHODS: Healthy volunteers were randomly assigned to start with either licorice or a control product in a nonblinded, 2 × 2 crossover study. Home BP was measured daily, and blood samples were collected at the end of each 2-wk period. RESULTS: There were 28 participants and no dropouts. The median age was 24.0 y (interquartile range 22.8-27.0 y). During the licorice compared with control intake period, the systolic home BP increased [mean difference: 3.1 mm Hg (95% confidence interval [CI]: 0.8, 5.4 mm Hg) compared with -0.3 mm Hg (95% CI: -1.8, 1.3 mm Hg); P = 0.018] and renin and aldosterone were suppressed [mean change: -30.0% (95% CI: -56.7%, -3.3%) compared with 15.8% (95% CI: -12.8%, 44.4%); P = 0.003; and -45.1% (95% CI: -61.5%, -28.7%) compared with 8.2% (95% CI: -14.7%, 31.1%); P <0.001, respectively]. In the quartile of participants with the most pronounced suppression of renin and aldosterone, N-terminal prohormone of brain natriuretic peptide concentration increased during the licorice compared with control period [mean change: 204.1% (95% CI: -11.6%, 419.7%) compared with 72.4% (95% CI: -52.2%, 197.1%); P = 0.016]. CONCLUSIONS: We found licorice to be more potent than previously known, with significant increases in BP, after a daily intake of only 100 mg GA. Thus, the safe limit of intake of this substance might need to be reconsidered. This trial was registered at clinicaltrials.gov as NCT05661721 (https://clinicaltrials.gov/study/NCT05661721).

Dynamic changes in renal sodium handling during sympathetic stimulation in healthy human males.

The temporal response of changes in renal sodium reabsorption during increased renal sympathetic nerve activity has not been investigated. Central hypovolemia by application of lower-body negative-pressure (LBNP) elicits baroreceptor mediated sympathetic reflexes to maintain arterial blood pressure. We hypothesized, that during 90 min LBNP, the renal sodium retention would increase rapidly, remain increased during intervention, and return to baseline immediately after end of intervention. METHODS: 30 young, healthy, sodium loaded, non-obese males were exposed to -15 mmHg LBNP, -30 mmHg LBNP, -15 mmHg LBNP + renin blockade or time-control (0 mmHg LBNP) for 90 min. Urine was collected every 15 min during 90 min of intervention and 60 min of recovery to identify a possible relation between time of intervention and renal response. RESULTS: All intervention groups exhibited a comparable reduction in distal sodium excretion at the end of the intervention (P = 0.46 between groups; -15 mmHg: -3.1 ± 0.9 %, -30 mmHg: -2.9 ± 0.6 %, -15 mmHg + aslikiren: -1.8 ± 0.6 %). -15 mmHg+Aliskiren resulted in a slower onset, but all groups exhibited a continued reduction in sodium excretion after 1 h of recovery despite return to baseline of renin, aldosterone, diuresis and cardiovascular parameters. CONCLUSION: Sympathetic stimulation for 90 min via LBNP at -30 mmHg LBNP compared to -15 mmHg did not result in a greater response in fractional Na+ excretion, suggesting that additional baroreceptor unloading did not cause further increases in renal sodium reabsorption. Changes in distal Na+ excretion were linear with respect to time (dose) of intervention, but seem to exhibit a saturation-like effect at a level around 4 %. The lack of recovery after 1 h is also a new finding that warrants further investigation.

Effects of Aliskiren Monotherapy versus Amlodipine Monotherapy in Hypertensive Patients with Obesity or Type 2 Diabetes Mellitus.

INTRODUCTION: Renin-angiotensin system inhibitors have been reported to exert protective effects against organ damage and failure; however, the impact of the direct renin inhibitor as monotherapy has not been assessed. Here, we investigated the effects of 24-week monotherapy with aliskiren compared to amlodipine in hypertensive patients with type 2 diabetes or obesity. METHODS: In this randomized intervention study, 62 adult hypertensive patients with visceral obesity (defined as a body mass index [BMI] greater than 25 kg/m2 and a visceral adipose tissue area [VFA] greater than 100 cm2) or type 2 diabetes mellitus (age 57 ± 13, 65% men, BMI 28.8 ± 4.8 kg/m2, VFA 134.8 ± 47.0 cm2, blood pressure 141 ± 16/86 ± 13 mm Hg) were randomized to receive 24-week treatment with aliskiren (max. 300 mg) or amlodipine (max. 10 mg). The primary outcome was the change in VFA at 24 weeks post-treatment. RESULTS: Change in VFA did not differ significantly from baseline in either group. Systolic blood pressure significantly decreased at 12 weeks (-10 mm Hg, p = 0.001) and 24 weeks (-10 mm Hg, p = 0.001) in the amlodipine group and at 24 weeks (-11 mm Hg, p = 0.001) in the aliskiren group. Diastolic blood pressure significantly decreased at 24 weeks (-6 mm Hg, p = 0.009) only in the amlodipine group. Although the estimated glomerular filtration rates did not significantly change in either group, the logarithm of urinary albumin excretion significantly decreased at 24 weeks only in the aliskiren group (-0.60, p < 0.001). The 24-week changes in the urinary albumin excretion significantly correlated with the changes in the plasma renin activity in the aliskiren group (r = 0.51, p = 0.008). CONCLUSION: Aliskiren monotherapy did not show any superiority to amlodipine monotherapy on VFA, estimated glomerular filtration rates, or urinary albumin excretion in obese or type 2 diabetic hypertensive patients.

Evaluating phase II results of Baxdrostat, an aldosterone synthase inhibitor for hypertension.

INTRODUCTION: Hypertension, a global health concern, poses a significant risk for other cardiovascular diseases. While lifestyle modifications and interventions like the Dietary Approaches to Stop Hypertension (DASH) diet offer some respite, their maintenance can be challenging. Recently, the spotlight has turned toward the renin-angiotensin-aldosterone system, a crucial player in the pathophysiology of hypertension. Contrary to other drugs, Baxdrostat, an innovative aldosterone synthase inhibitor (ASI), targets aldosterone synthesis, mitigating negative systemic effects. AREAS COVERED: Baxdrostat showcases rapid absorption, high oral bioavailability, and significant selectivity for aldosterone synthase which presents a proactive approach to hypertension management by reducing aldosterone levels. Early trials have demonstrated its potential in lowering blood pressure in resistant hypertension cases. Current clinical trials are also exploring its application in primary aldosteronism and chronic kidney disease, with preliminary findings indicating its promise as a novel antihypertensive agent. This article encapsulates the current state of knowledge regarding Baxdrostat, encompassing its uses, ongoing clinical trials, and potential future clinical applications. EXPERT OPINION: Future research endeavors will play a pivotal role in unveiling the effectiveness and safety profile of this novel medication. Thus, positioning the baxdrostat as a valuable addition to the armamentarium of antihypertensive agents, especially for patients with complex, multifactorial hypertensive conditions.

Safety and efficacy of new potassium binders on hyperkalemia management in patients with heart failure: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Hyperkalemia leads to suboptimal use of evidence-based therapies in patients with heart failure (HF). Therefore, we aimed to assess whether new potassium binders are effective and safe to promote medical optimization in patients with HF. METHODS: MEDLINE, Cochrane, and Embase were searched for randomized controlled trials (RCTs) that reported outcomes after initiation of Patiromer or Sodium Zirconium Cyclosilicate (SZC) versus placebo in patients with HF at high risk of hyperkalemia development. Risk ratios (RR) with 95% confidence intervals (CI) were pooled with a random effects model. Quality assessment and risk of bias were performed according to Cochrane recommendations. RESULTS: A total of 1432 patients from 6 RCTs were included, of whom 737 (51.5%) patients received potassium binders. In patients with HF, potassium binders increased the use of renin-angiotensin-aldosterone inhibitors (RR 1.14; 95% CI 1.02-1.28; p = 0.021; I2 = 44%) and reduced the risk of hyperkalemia (RR 0.66; 95% CI 0.52-0.84; p < 0.001; I2 = 46%). The risk of hypokalemia was significantly increased in patients treated with potassium binders (RR 5.61; 95% CI 1.49-21.08; p = 0.011; I2 = 0%). There was no difference between groups in all-cause mortality rates (RR 1.13; 95% CI 0.59-2.16; p = 0.721; I2 = 0%) or in adverse events leading to drug discontinuation (RR 1.08; 95% CI 0.60-1.93; p = 0.801; I2 = 0%). CONCLUSION: The use of new potassium binders Patiromer or SZC in patients with HF at risk for hyperkalemia increased the rates of medical therapy optimization with renin-angiotensin-aldosterone inhibitors and reduced the incidence of hyperkalemia, at the cost of an increased prevalence of hypokalemia.

Improvement in Blood Pressure After Intermittent Fasting in Hipertension: Could Renin-Angiotensin System and Autonomic Nervous System Have a Role? / Melhora da Pressão Arterial após Jejum Intermitente na Hipertensão: O Sistema Renina-Angiotensina e o Sistema Nervoso Autônomo Podem Funcionar?

BACKGROUND: Although it has been reported that the intermittent fasting (IF) diet has positive effects on heart health and improvement in blood pressure, it has not been sufficiently clarified how it could have these positive effects yet. OBJECTIVE: We aimed to evaluate the effects of IF on the autonomic nervous system (ANS) and renin-angiotensin system (RAS), which are closely related to blood pressure. METHODS: Seventy-two hypertensive patients were included in the study, and the data of 58 patients were used. All the participants fasted for about 15-16 hours for 30 days. Participants were evaluated with 24-hour ambulatory blood pressure monitoring and Holter electrocardiography before and after IF; also, 5 ml venous blood samples were taken for assessment of Serum angiotensin I (Ang-I) and angiotensin II (Ang-II) levels and angiotensin-converting enzyme (ACE) activity. For data analysis, the p-value <0.05 was accepted as significant. RESULTS: Compared to pre-IF, a significant decrease was observed in the patients' blood pressures in post-IF. An increase in high-frequency (HF) power and the mean root square of the sum of squares of differences between adjacent NN intervals (RMSSD) were observed after the IF protocol (p=0.039, p=0.043). Ang-II and ACE activity were lower in patients after IF (p=0.034, p=0.004), and decreasing Ang-II levels were determined as predictive factors for improvement of the blood pressure, like the increase in HF power and RMSSD. CONCLUSION: The present findings of our study demonstrated an improvement in blood pressure and the relationship of blood pressure with positive outcomes, including HRV, ACE activity, and Ang-II levels after the IF protocol.

FUNDAMENTO: Embora tenha sido relatado que a dieta de jejum intermitente (JI) tem efeitos positivos na saúde do coração e na melhora da pressão arterial, ainda não foi suficientemente esclarecido como poderia ter esses efeitos positivos.Objetivo: Nosso objetivo foi avaliar os efeitos do JI no sistema nervoso autônomo (SNA) e no sistema renina-angiotensina (SRA), que estão intimamente relacionados à pressão arterial. MÉTODOS: Setenta e dois pacientes hipertensos foram incluídos no estudo, e os dados de 58 pacientes foram usados. Todos os participantes jejuaram por cerca de 15-16 horas por 30 dias. Os participantes foram avaliados com monitorização ambulatorial da pressão arterial de 24 horas e eletrocardiograma Holter antes e após o JI; também, amostras de sangue venoso de 5 ml foram coletadas para avaliação dos níveis séricos de angiotensina I (Ang-I) e angiotensina II (Ang-II) e da atividade da enzima conversora de angiotensina (ECA). Para análise dos dados, o valor de p < 0,05 foi aceito como significativo. RESULTADOS: Comparado ao pré-JI, observou-se queda significativa nas pressões arteriais dos pacientes no pós-JI. Um aumento na potência de alta frequência (AF) e na raiz quadrada média da soma dos quadrados das diferenças entre intervalos NN adjacentes (RMSSD) foram observados após o protocolo JI (p=0,039, p=0,043). A Ang-II e a atividade da ECA foram menores em pacientes após JI (p=0,034, p=0,004), e níveis decrescentes de Ang-II foram determinados como fatores preditivos para melhora da pressão arterial, como o aumento da potência de AF e RMSSD. CONCLUSÃO: Os presentes achados de nosso estudo demonstraram uma melhora na pressão arterial e a relação da pressão arterial com resultados positivos, incluindo VFC, atividade da ECA e níveis de Ang-II após o protocolo JI.

Exercise Training Prevents High Fructose-Induced Hypertension and Renal Damages in Male Dahl Salt-Sensitive Rats.

INTRODUCTION: High-fructose diet (HFr) causes metabolic syndrome, and HFr-induced hypertension and renal damage are exaggerated in Dahl salt-sensitive (DS) rats. Exercise training (Ex) has antihypertensive and renal protective effects in rats fed HFr; however, there has been little discussion about the DS rats, which exhibit metabolic disturbances. This study thus examined the effects of Ex on DS rats fed HFr. METHODS: Male DS rats were divided into three groups. The control group was fed a control diet, and both the HFr group and the HFr-Ex group were fed an HFr (60% fructose). The HFr-Ex group also underwent treadmill running (20 m·min -1 , 60 min·d -1 , 5 d·wk -1 ). After 12 wk, renal function, histology, and renin-angiotensin system were examined. RESULTS: HFr increased blood pressure, urinary albumin, and creatinine clearance, and Ex inhibited these increases. HFr induced glomerular sclerosis, podocyte injury, afferent arteriole thickening, and renal interstitial fibrosis, and Ex ameliorated them. HFr reduced plasma renin activity, and Ex further reduced the activity. HFr also increased the expression of angiotensinogen, renin, angiotensin-converting enzyme (ACE), and angiotensin II type 1 receptor, and Ex restored the ACE expression to the control levels. HFr decreased the expression of ACE2, angiotensin II type 2 receptor, and Mas receptor, and Ex restored the ACE2 and Mas receptor expressions to the control levels and further decreased the angiotensin II type 2 receptor expression. HFr increased the ACE activity and decreased the ACE2 activity, and Ex restored these activities to the control levels. CONCLUSIONS: Ex prevents HFr-induced hypertension and renal damages in DS rats. The changes in renal renin-angiotensin system may be involved in the mechanism of the antihypertensive and renal protective effects of Ex.

Effects of Long-Term Intervention with Losartan, Aspirin and Atorvastatin on Vascular Remodeling in Juvenile Spontaneously Hypertensive Rats.

Hypertension in adolescents is associated with adverse cardiac and vascular events. In addition to lowering blood pressure, it is not clear whether pharmacological therapy in early life can improve vascular remodeling. This study aimed to evaluate the effects of long-term administration of losartan, aspirin, and atorvastatin on vascular remodeling in juvenile spontaneously hypertensive rats (SHRs). Losartan, aspirin, and atorvastatin were administered via gavage at doses of 20, 10, and 10 mg/kg/day, respectively, on SHRs aged 6-22 weeks. Paraffin sections of the blood vessels were stained with hematoxylin-eosin (H&E) and Sirius Red to evaluate the changes in the vascular structure and the accumulation of different types of collagen. The plasma levels of renin, angiotensin II (Ang II), aldosterone (ALD), endothelin-1 (ET-1), interleukin-6 (IL-6), and neutrophil elastase (NE) were determined using ELISA kits. After the 16-week treatment with losartan, aspirin, and atorvastatin, the wall thickness of the thoracic aorta and carotid artery decreased. The integrity of the elastic fibers in the tunica media was maintained in an orderly manner, and collagen deposition in the adventitia was retarded. The plasma levels of renin, ALD, ET-1, IL-6, and NE in the SHRs also decreased. These findings suggest that losartan, aspirin, and atorvastatin could improve vascular remodeling beyond their antihypertensive, anti-inflammatory, and lipid-lowering effects. Many aspects of the protection provided by pharmacological therapy are important for the prevention of cardiovascular diseases in adults and older adults.

Beneficial effects of Panax notoginseng (Burkill) F. H. Chen flower saponins in rats with metabolic hypertension by inhibiting the activation of the renin-angiotensin-aldosterone system through complement 3.

BACKGROUND: Metabolic hypertension (MH) has become the most common type of hypertension in recent years due to unhealthy eating habits and lifestyles of people, such as over-eating alcohol, high fat, and sugar diets (ACHFSDs). Therefore, effective means to combat MH are needed. Previous studies have shown that Panax notoginseng (Burkill) F. H. Chen flower saponins (PNFS) can lower blood pressure in spontaneously hypertensive rats (SHR). However, whether it acts on MH and its mechanism of action remain unclear.  METHODS: The pharmacodynamic effects of PNFS were evaluated in rats with ACHFSDs-induced MH. The blood pressure, blood biochemical, grip strength, face temperature, vertigo time, and liver index were estimated. The histological changes in the liver and aorta were observed using hematoxylin and eosin staining. The levels of ET-1, TXB2, NO, PGI2, Renin, ACE, Ang II, and ALD in plasma were detected using ELISA. The levels of C3, KLF5, LXRα, and Renin in kidney tissues were measured using qRT-PCR.The expression levels of C3, KLF5, LXRα, and Renin in kidney tissues were examined using Western blotting. RESULTS: In the present study, PNFS was found to reduce blood pressure, face temperature, and vertigo time, increase grip strength and improve dyslipidemia in rats with MH. In addition, PNFS decreased the plasma levels of ET-1 and TXB2, elevated the levels of NO and PGI2, and improved pathological aortic injury. Meanwhile, PNFS decreased the plasma levels of Renin, ACE, Ang II, and ALD. QRT-PCR and Western bolt showed that PNFS downregulated C3, KLF5, LXRα, and Renin protein and mRNA expression in the kidneys of rats with MH. CONCLUSION: The finding of the present study suggested that PNFS could downregulate C3 and KLF-5 expression in rats with MH, thereby inhibiting the overactivation of the renin-angiotensin-aldosterone system, while improving vascular endothelial function and ultimately reducing blood pressure in rats with MH.

Evaluating Guideline Directed Medical Therapy in Patients With Heart Failure With Reduced Ejection Fraction Post-coronary Artery Bypass Grafting.

Background: Limited evidence regarding the use of guideline directed medical therapy (GDMT) in patients with heart failure with reduced ejection fraction (HFrEF) undergoing coronary artery bypass grafting (CABG) is available. Objective: The purpose of this study was to characterize prescription of HFrEF GDMT use before and after CABG. Methods: A retrospective analysis of adult patients with an ejection fraction ≤40% undergoing CABG was performed. The primary objective was to evaluate patients receiving HFrEF GDMT, defined as a heart failure beta-blocker (HFBB) and a renin-angiotensin inhibitor preoperatively and postoperatively. Secondary outcomes included dosing, percent of patients on each individual therapy, mineralocorticoid receptor antagonist (MRA) use, and the combination thereof. The follow up period was 1 year. Results: Thirty-eight patients met criteria for inclusion. Prior to CABG, 52.6% of patients were receiving HFrEF GDMT. The prescribing rate of HFrEF GDMT was not significantly higher at any point within 1 year postoperatively (P = .299). The rate of renin-angiotensin inhibitors, HFBB, and aldosterone antagonists use significantly increased from 13.2% preoperatively to 36.8% at 1 year after CABG (P = .022). Doses of individual therapies were not significantly different across all time points preoperatively and postoperatively. Conclusion: HFrEF GDMT use and doses of individual therapies after CABG were not maximized. Collaborative efforts between cardiac surgeons, heart failure cardiologists, and pharmacists could be used to optimize HFrEF GDMT use and dose titration.

Uric acid accumulation in the kidney triggers mast cell degranulation and aggravates renal oxidative stress.

The accumulation of uric acid (UA) in the body can lead to the occurrence of hyperuricemia or uric acid nephropathy. Mast cells (MCs) increase oxidative stress and release renin to promote the production of Ang II. The aim of this study was to investigate the effect of UA on MCs in rat kidneys and the association between MCs and renal injury. Our results show that UA accumulation in the kidney stimulated the degranulation of MCs and the release of renin to promote Ang II production, resulting in renal oxidative stress, mitochondrial structural damage, and microvascular system damage. The expression of urate-related transporters was regulated by the UA level and serum urinary toxins levels were substantially elevated in hyperuricemia. Administration of the MCs membrane stabilizer sodium cromoglycate (SCG) or the angiotensin receptor antagonist Valsartan decreased the production of renin and Ang II and relieved renal oxidative stress, mitigated mitochondrial structural damage and microvascular system damage, and promoted the excretion of UA and urinary toxins by increasing the expression of urate-related transporters. These results demonstrate that the accumulation of UA in the kidney can trigger the degranulation of MCs and promote the development of renal oxidative stress. Administration of SCG and Valsartan ameliorated UA-induced renal injury by inhibiting MCs degranulation and reducing renal oxidative stress by inhibiting renin and Ang II production and accelerating renal clearance of UA and uremic toxins.

Plasma Renin-guided Therapy in Patients of Primary Hypertension on Antihypertensives: A Prospective Cohort Study.

BACKGROUND: Most guidelines for hypertension overlook the underlying pathophysiologic basis in deciding antihypertensives. Based on renin levels, hypertension may be classified as high-renin hypertension (HRH), low-renin hypertension (LRH), and normal-renin hypertension (NRH). The study examined the renin levels in a hypertensive population and assessed the effect of renin-guided antihypertensive management on blood pressure (BP) control. MATERIALS AND METHODS: This study was a single-center prospective cohort study. Subjects with primary hypertension (aged 20-60 years) on antihypertensives were included in the study. Initial BP was recorded and subsequently, all antihypertensives were discontinued. After 2 weeks, second BP was recorded and plasma renin assay (PRA) sample was collected. All patients were restarted on the previous antihypertensives and further modification of medication was performed based on their PRA. Anti V drugs, such as diuretics and calcium channel blockers (CCBs) were used in LRH while beta-blockers and antirenin drugs (Anti R drugs) were used in HRH. RESULTS: The study included 918 patients with hypertension and 896 cases were finally analyzed. Of these patients, 287 (32.03%) had LRH (<0.51 ng/mL/hr), 412 (45.98%) had HRH (>2.64 ng/mL/hr), while 197 (21.99%) had NRH (0.51-2.64 ng/mL/hr). Renin-guided management caused significant BP reduction. In controlled BP group, the systolic BP (SBP)/diastolic BP (DBP) before and after modification were 133.83 ± 3.36/84.77 ± 3.12 and 123.87 ± 10.59/84.05 ± 1.84, respectively (p-value < 0.05). In uncontrolled BP group, the corresponding SBP/DBP were 152.17 ± 2.95/90.36 ± 5.02 and 138 ± 1.23/87.78 ± 0.84, respectively (p-value < 0.05). The number of hypertensives used in patients also reduced with reduction in patients on two, three, or four drugs. CONCLUSIONS: Renin-guided therapy is useful for improving BP control in both controlled and uncontrolled hypertensive patients and in reducing the number of antihypertensive drugs.

Sustained activation of the renin-angiotensin-aldosteron system after fetal exposure to AT1 blockers: Effects on kidney and bone in a preterm newborn.

The renin-angiotensin-aldosterone system (RAAS) plays a key role in development of fetal kidney. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor type 1 (AT1) antagonists alter RAAS-signaling compromising metanephrogenesis, and vascular and tubular development. The result is a fetal "RAS blockage syndrome" that may occur not only following exposure during the second and third trimester, but also after the use of these drugs at the beginning of pregnancy. The in-utero exposure to AT1 antagonists is not confined exclusively to the risk of neonatal renal failure, but also to skull ossification defect that worsens the neonatal prognosis. We report the case of early arterial hypertension development, marked increase of plasma renin and aldosterone, severe hypocalvaria, and low bone mineralization in a female preterm infant in-utero exposed to AT1 antagonists.

Rapid decrease in eGFR with concomitant use of tyrosine kinase inhibitors and renin-aldosterone-angiotensin system inhibitors in patients with chronic myelogenous leukemia.

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). However, TKI-related chronic renal toxicity has been reported, particularly in patients with hypertension. We assessed whether incidental use of specific types of antihypertensive drugs, including renin-aldosterone-angiotensin system inhibitors (RAASis), affects the change in estimated glomerular filtration rate (eGFR) during TKI treatment. We retrospectively analyzed all eGFR measurements during TKI treatment for 142 CML patients at Kyushu University Hospital, estimating the rate of eGFR change using a mixed-effects model. Overall, a significant interaction was found between the type of antihypertensive medication used and the yearly change in eGFR (P < 0.01), with RAASi users exhibiting the most rapid decrease in eGFR (- 5.5%/year). The analysis by TKI used showed that the interaction was significant only in imatinib and bosutinib users (P < 0.01 and P = 0.04, respectively). The yearly rate of eGFR decrease was the most notable in RAASi users, at - 5.7 (- 6.6, - 4.9) and - 10.1 (- 12.3, - 7.9) for imatinib and bosutinib users, respectively. Our findings indicate that eGFR should be carefully monitored in patients taking these TKIs.

Discovery of SPH3127: A Novel, Highly Potent, and Orally Active Direct Renin Inhibitor.

Renin is the rate-limiting enzyme in the renin-angiotensin-aldosterone system (RAAS) which regulates blood pressure and renal function and hence is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. However, the development of direct renin inhibitors (DRIs) with favorable oral bioavailability has been a longstanding challenge for many years. This problem was thought to be because most of the reported DRIs were peptide-like structures or nonpeptide-like structures with a molecular weight (MW) of > 600. Therefore, we tried to find nonpeptidomimetic DRIs with a MW of < 500 and discovered the promising 2-carbamoyl morpholine derivative 4. In our efforts to improve the pharmacokinetic profile of 4 without a significant increase in the MW, we discovered compound 18 (SPH3127), which demonstrated higher bioavailability and a more potent antihypertensive effect in preclinical models than aliskiren and has completed a phase II clinical trial for essential hypertension.

Novel intrauterine growth retardation model: effects of maternal subtotal nephrectomy on neonates.

Changes in body weight (BW), systolic blood pressure (SBP), and localization of renin in the kidneys of neonates born to normal mothers (C neonates) or to five-sixths (5/6) nephrectomized (2/3 left kidney and right kidney) mothers (Nx neonates) were studied. Maternal 5/6 nephrectomy caused weight loss in neonates but no differences in SBP or renin localization. Culling Nx neonates to a litter of 3 at 1 day after birth resulted in growth catching up with C neonates from 3 weeks old and increases in both SBP and renin-positive cells in neonatal kidney. These findings revealed that maternal 5/6 nephrectomy results in low-birth-weight neonates and that these neonates are at increased risk of metabolic syndrome by catch-up growth.

Interactive effects of high temperature and pesticide exposure on oxidative status, apoptosis, and renin expression in kidney of goldfish: Molecular and cellular mechanisms of widespread kidney damage and renin attenuation.

One of many noteworthy consequences of increasing societal reliance on pesticides is their predominance in aquatic environments. These pernicious chemicals interact with high temperatures from global climate change, heat waves, and natural variations to create unstable environments that negatively impact organisms' health. To understand these conditions, we examined the dose-dependent effects of environmentally relevant pesticide mixtures (metolachlor, linuron, isoproturon, tebuconazole, aclonifen, atrazine, pendimethalin, and azinphos-methyl) combined with elevated temperatures (22 control vs. 32°C for 4-week exposure) on renin, dinitrophenyl protein (DNP, an indicator of reactive oxygen species, ROS), 3-nitrotyrosine protein (NTP, an indicator of reactive nitrogen species, RNS), superoxidase dismutase (SOD, an antioxidant), and catalase (CAT, an antioxidant) expressions in the kidneys of goldfish (Carassius auratus). Histopathological analysis showed widespread damage to kidney tissues in high temperature and pesticide co-exposure groups, including rupture of the epithelial layer, hemorrhaging, and degeneration of tubular epithelium. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical analyses demonstrated significant declines in renin receptor-like mRNA and protein expressions in kidney tissues under combined exposure to high temperature and pesticides compared with controls; conversely, expression of DNP, NTP, SOD, and CAT increased in kidney tissues under the same conditions. Apoptotic cells were also increased in co-exposure groups as assessed by in situ terminal deoxynucleotidyl transferase dUTP nick labeling (TUNEL) assay. The enhanced apoptosis in kidneys of heat and pesticides co-exposed fish was associated with increased caspase-3 (a protease enzyme) mRNA levels. Our results demonstrated that high temperature and pesticides induced oxidative/nitrative stress (i.e., ROS/RNS), damaged tissues, increased cellular apoptosis, and suppressed renin expression in kidneys of goldfish.

Cross-Talk between the (Endo)Cannabinoid and Renin-Angiotensin Systems: Basic Evidence and Potential Therapeutic Significance.

This review is dedicated to the cross-talk between the (endo)cannabinoid and renin angiotensin systems (RAS). Activation of AT1 receptors (AT1Rs) by angiotensin II (Ang II) can release endocannabinoids that, by acting at cannabinoid CB1 receptors (CB1Rs), modify the response to AT1R stimulation. CB1R blockade may enhance AT1R-mediated responses (mainly vasoconstrictor effects) or reduce them (mainly central nervous system-mediated effects). The final effects depend on whether stimulation of CB1Rs and AT1Rs induces opposite or the same effects. Second, CB1R blockade may diminish AT1R levels. Third, phytocannabinoids modulate angiotensin-converting enzyme-2. Additional studies are required to clarify (1) the existence of a cross-talk between the protective axis of the RAS (Ang II-AT2 receptor system or angiotensin 1-7-Mas receptor system) with components of the endocannabinoid system, (2) the influence of Ang II on constituents of the endocannabinoid system and (3) the (patho)physiological significance of AT1R-CB1R heteromerization. As a therapeutic consequence, CB1R antagonists may influence effects elicited by the activation or blockade of the RAS; phytocannabinoids may be useful as adjuvant therapy against COVID-19; single drugs acting on the (endo)cannabinoid system (cannabidiol) and the RAS (telmisartan) may show pharmacokinetic interactions since they are substrates of the same metabolizing enzyme of the transport mechanism.