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The renin‐angiotensin system (RAS) is an endocrine system composed of two main axes: the classical and the counterregulatory, very often displaying opposing effects. The classical axis, primarily mediated by angiotensin receptors type 1 (AT1R), is linked to obesity‐associated metabolic effects. On the other hand, the counterregulatory axis appears to exert antiobesity effects through the activation of two receptors, the G protein‐coupled receptor (MasR) and Mas‐related receptor type D (MrgD). The local RAS in adipose organ has prompted extensive research into white adipose tissue and brown adipose tissue (BAT), with a key role in regulating the cellular and metabolic plasticity of these tissues. The MasR activation favors the brown plasticity signature in the adipose organ by improve the thermogenesis, adipogenesis, and lipolysis, decrease the inflammatory state, and overall energy homeostasis. The MrgD metabolic effects are related to the maintenance of BAT functionality, but the signaling remains unexplored. This review provides a summary of RAS counterregulatory actions triggered by Mas and MrgD receptors on adipose tissue plasticity. Focus on the effects related to the morphology and function of adipose tissue, especially from animal studies, will be given targeting new avenues for treatment of obesity‐associated metabolic effects. [ABSTRACT FROM AUTHOR]

Hyperkalaemia is an electrolyte imbalance that impairs muscle function and myocardial excitability, and can potentially lead to fatal arrhythmias and sudden cardiac death. The prevalence of hyperkalaemia is estimated to be 6%–7% worldwide and 7%–10% in Asia. Hyperkalaemia frequently affects patients with chronic kidney disease, heart failure, and diabetes mellitus, particularly those receiving treatment with renin‐angiotensin‐aldosterone system (RAAS) inhibitors. Both hyperkalaemia and interruption of RAAS inhibitor therapy are associated with increased risks for cardiovascular events, hospitalisations, and death, highlighting a clinical dilemma in high‐risk patients. Conventional potassium‐binding resins are widely used for the treatment of hyperkalaemia; however, caveats such as the unpalatable taste and the risk of gastrointestinal side effects limit their chronic use. Recent evidence suggests that, with a rapid onset of action and improved gastrointestinal tolerability, novel oral potassium binders (e.g., patiromer and sodium zirconium cyclosilicate) are alternative treatment options for both acute and chronic hyperkalaemia. To optimise the care for patients with hyperkalaemia in the Asia–Pacific region, a multidisciplinary expert panel was convened to review published literature, share clinical experiences, and ultimately formulate 25 consensus statements, covering three clinical areas: (i) risk factors of hyperkalaemia and risk stratification in susceptible patients; (ii) prevention of hyperkalaemia for at‐risk individuals; and (iii) correction of hyperkalaemia for at‐risk individuals with cardiorenal disease. These statements were expected to serve as useful guidance in the management of hyperkalaemia for health care providers in the region. [ABSTRACT FROM AUTHOR]

Introduction: Results on the association between the use of renin–angiotensin system blockades (RASBs) and vascular access-related outcomes are inconsistent. We aimed to compare vascular access-related outcomes according to the use of RASBs in hemodialysis patients. Methods: This study used data from a national hemodialysis quality assessment program of the Republic of Korea (n = 54,903). Group 1 was not prescribed any blood pressure-lowering drugs (n = 28,521). Group 2 was prescribed other blood pressure-lowering agents except for RASBs (n = 9571). Group 3 was prescribed RASBs (n = 16,811). Vascular access-related outcomes were classified into intervention-free survival (IFS), thrombosis-free survival (TFS), and vascular access survival (VAS). Results: No significant difference in the three access survival rates was identified among the three groups. The multivariate Cox regression analyses indicated that Group 3 had better outcomes in IFS and TFS than Group 1. The numbers of angioplasties performed were significantly greater in Group 1 than in the other two groups. The numbers of thrombectomies performed were significantly the lowest in Group 3 among all the groups. Conclusions: Our study revealed different results according to types of access survival in univariate or multivariate analyses. The association of RASBs with favorable outcomes in vascular access remains unclear. [ABSTRACT FROM AUTHOR]

The renin‐angiotensin system (RAS) plays a key role in blood pressure regulation. The RAS is a complex interconnected system composed of two axes with opposite effects. The pressor arm, represented by angiotensin (Ang) II and the AT1 receptor (AT1R), mediates the vasoconstrictor, proliferative, hypertensive, oxidative, and pro‐inflammatory effects of the RAS, while the depressor/protective arm, represented by Ang‐(1–7), its Mas receptor (MasR) and the AT2 receptor (AT2R), opposes the actions elicited by the pressor arm. The AT1R, AT2R, and MasR belong to the G‐protein‐coupled receptor (GPCR) family. GPCRs operate not only as monomers, but they can also function in dimeric (homo and hetero) or higher‐order oligomeric states. Due to the interaction with other receptors, GPCR properties may change: receptor affinity, trafficking, signaling, and its biological function may be altered. Thus, heteromerization provides a newly recognized means of modulation of receptor function, as well as crosstalk between GPCRs. This review is focused on angiotensin receptors, and how their properties are influenced by crosstalk with other receptors, adding more complexity to an already complex system and potentially opening up new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Obesity over‐activates the classical arm of the renin‐angiotensin system (RAS), impairing skeletal muscle remodeling. We aimed to compare the effect of exercise training and enalapril, an angiotensin‐converting enzyme inhibitor, on RAS modulation in the skeletal muscle of obese animals. Thus, we divided C57BL/6 mice into two groups: standard chow (SC) and high‐fat (HF) diet for 16 weeks. At the eighth week, the HF‐fed animals were divided into four subgroups—sedentary (HF), treated with enalapril (HF‐E), exercise training protocol (HF‐T), and combined interventions (HF‐ET). After 8 weeks of treatment, we evaluated body mass and index (BMI), body composition, exercise capacity, muscle morphology, and skeletal muscle molecular markers. All interventions resulted in lower BMI and attenuation of overactivation in the classical arm, while favoring the B2R in the bradykinin receptors profile. This was associated with reduced apoptosis markers in obese skeletal muscles. The HF‐T group showed an increase in muscle mass and expression of biosynthesis markers and a reduction in expression of degradation markers and muscle fiber atrophy due to obesity. These findings suggest that the combination intervention did not have a synergistic effect against obesity‐induced muscle remodeling. Additionally, the use of enalapril impaired muscle's physiological adaptations to exercise training. [ABSTRACT FROM AUTHOR]

Renin is the key enzyme of the systemic renin–angiotensin–aldosterone system, which plays an essential role in regulating blood pressure and maintaining electrolyte and extracellular volume homeostasis. Renin is mainly produced and secreted by specialized juxtaglomerular (JG) cells in the kidney. In the present study, we report for the first time that the conserved transmembrane receptor neuropilin‐1 (NRP1) participates in the development of JG cells and plays a key role in renin production. We used the myelin protein zero‐Cre (P0‐Cre) to abrogate Nrp1 constitutively in P0‐Cre lineage‐labelled cells of the kidney. We found that the P0‐Cre precursor cells differentiate into renin‐producing JG cells. We employed a lineage‐tracing strategy combined with RNAscope quantification and metabolic studies to reveal a cell‐autonomous role for NRP1 in JG cell function. Nrp1‐deficient animals displayed abnormal levels of tissue renin expression and failed to adapt properly to a homeostatic challenge to sodium balance. These findings provide new insights into cell fate decisions and cellular plasticity operating in P0‐Cre–expressing precursors and identify NRP1 as a novel key regulator of JG cell maturation. Key points: Renin is a centrepiece of the renin–angiotensin–aldosterone system and is produced by specialized juxtaglomerular cells (JG) of the kidney.Neuropilin‐1 (NRP1) is a conserved membrane‐bound receptor that regulates vascular and neuronal development, cancer aggressiveness and fibrosis progression.We used conditional mutagenesis and lineage tracing to show that NRP1 is expressed in JG cells where it regulates their function.Cell‐specific Nrp1 knockout mice present with renin paucity in JG cells and struggle to adapt to a homeostatic challenge to sodium balance.The results support the versatility of renin‐producing cells in the kidney and may open new avenues for therapeutic approaches. [ABSTRACT FROM AUTHOR]

Depression is a mood disorder characterized by abnormal thoughts. The pathophysiology of depression is related to the deficiency of serotonin (5HT), which is derived from tryptophan (Trp). Mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of depression. Notably, the renin–angiotensin system (RAS) is involved in the pathogenesis of depression, and different findings revealed that angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may be effective in depression. However, the underlying mechanism for the role of dysregulated brain RAS‐induced depression remains speculative. Therefore, this review aimed to revise the conceivable role of ACEIs and ARBs and how these agents ameliorate the pathophysiology of depression. Dysregulation of brain RAS triggers the development and progression of depression through the reduction of brain 5HT and expression of brain‐derived neurotrophic factor (BDNF) and the induction of mitochondrial dysfunction, oxidative stress, and neuroinflammation. Therefore, inhibition of central classical RAS by ARBS and ACEIs and activation of non‐classical RAS prevent the development of depression by regulating 5HT, BDNF, mitochondrial dysfunction, oxidative stress, and neuroinflammation. [ABSTRACT FROM AUTHOR]

The classical renin angiotensin aldosterone system (RAAS), as well as the recently described counter‐regulatory or non‐canonical RAAS have been well characterized for their role in cardiovascular homeostasis. Moreover, extensive research has been conducted over the past decades on both paracrine and the endocrine roles of local RAAS in various metabolic regulations and in chronic diseases. Clinical evidence from patients on RAAS blockers as well as pre‐clinical studies using rodent models of genetic manipulations of RAAS genes documented that this system may play important roles in the interplay between metabolic diseases and cancer, namely breast cancer. Some of these studies suggest potential therapeutic applications and repurposing of RAAS inhibitors for these diseases. In this review, we discuss the mechanisms by which RAAS is involved in the pathogenesis of metabolic diseases such as obesity and type‐2 diabetes as well as the role of this system in the initiation, expansion and/or progression of breast cancer, especially in the context of metabolic diseases. [ABSTRACT FROM AUTHOR]

Aim: Sodium‐glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real‐world practice remains unclear. Materials and Methods: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end‐stage kidney disease). Results: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow‐up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin‐angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (β = −0.609, p =.039; β = −2.298, p <.001; β = −0.936, p =.048; β = −0.079, p <.001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p <.001). Conclusions: The concomitant use of renin‐angiotensin system inhibitors and diuretics, higher urine protein levels and pre‐treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes. [ABSTRACT FROM AUTHOR]

The renin‐angiotensin system (RAS) regulates systemic and cerebral blood flow and is dysregulated in dementia. The major aim of this study was to determine if RAS signalling is dysregulated in vascular dementia. We measured markers of RAS signalling in white matter underlying the frontal and occipital cortex in neuropathologically confirmed cases of vascular dementia (n = 42), Alzheimer's disease (n = 50), mixed AD/VaD (n = 50) and age‐matched controls (n = 50). All cases were stratified according to small vessel disease (SVD) severity across both regions. ACE‐1 and ACE‐2 protein and activity was measured by ELISA and fluorogenic peptide assays respectively, and angiotensin peptide (Ang‐II, Ang‐III and Ang‐(1–7)) levels were measured by ELISA. ACE‐1 protein level and enzyme activity, and Ang‐II and Ang‐III, were elevated in the white matter in vascular dementia in relation to SVD severity. ACE‐1 and Ang‐II protein levels were inversely related to MAG:PLP1 ratio, a biochemical marker of brain tissue oxygenation that when reduced indicates cerebral hypoperfusion, in a subset of cases. ACE‐2 level was elevated in frontal white matter in vascular dementia. Ang‐(1–7) level was elevated across all dementia groups compared to age‐matched controls but was not related to SVD severity. RAS signalling was not altered in the white matter in Alzheimer's disease. In the overlying frontal cortex, ACE‐1 protein was reduced and ACE‐2 protein increased in vascular dementia, whereas angiotensin peptide levels were unchanged. These data indicate that RAS signalling is dysregulated in the white matter in vascular dementia and may contribute to the pathogenesis of small vessel disease. [ABSTRACT FROM AUTHOR]

Although diuretics play an important role in triple‐whammy acute kidney injury (AKI), it is unclear whether the type of diuretic influences the risk of triple‐whammy AKI. The aim of this study was to evaluate whether vasopressin receptor antagonists affect triple‐whammy AKI. This cross‐sectional study used disproportionality analysis of VigiBase data to assess the risk of AKI with various diuretics. Although multiple logistic regression analysis showed that aldosterone antagonists (odds ratio [OR] 2.19, 95% CI 2.01–2.37), loop diuretics (OR 4.40, 95% CI 4.07–4.76) and thiazide diuretics (OR 1.98, 95% CI 1.83–2.15) increased the risk of AKI in patients who received non‐steroidal anti‐inflammatory drugs (NSAIDs) and renin‐angiotensin system inhibitors (RASi), vasopressin receptor antagonists did not increase the risk of AKI in those patients. Vasopressin receptor antagonists might not influence the development of triple‐whammy AKI. [ABSTRACT FROM AUTHOR]

Background: Little evidence exists about the comparative effects of first‐line antihypertensive medications (i.e., renin‐angiotensin‐aldosterone converting enzyme inhibitors (RAASi), amlodipine, or thiazide diuretics) in older adults with limited life expectancy. We compared the rates of injurious falls and short‐term cardiovascular events between different first‐line antihypertensive medication classes in adults receiving care in nursing homes (NH). Methods: This was a retrospective cohort of Medicare fee‐for‐service beneficiaries receiving care in NHs. Patients newly dispensed first‐line antihypertensive medications were identified using Part D claims (2015–2018) and linked with clinical assessments (i.e., Minimum Data Set). Fall‐related injuries (FRI), hip fractures, and major adverse cardiac events (MACE) outcomes were identified using hospitalization claims. Patients were followed from the date of antihypertensive dispensing until the occurrence of outcomes, death, disenrollment, or 6‐month follow‐up. Inverse‐probability‐of‐treatment‐weighted (IPTW) cause‐specific hazards regression models were used to compare outcomes between patients who were new users of RAASi, amlodipine, or thiazides. Results: Our cohort included 16,504 antihypertensive users (RAASi, n = 9574; amlodipine, n = 5049; thiazide, n = 1881). Mean age was 83.5 years (± 8.2), 70.6% were female, and 17.2% were non‐white race. During a mean follow‐up of 5.3 months, 326 patients (2.0%) experienced an injurious fall, 1590 (9.6%) experienced MACE, and 2123 patients (12.9%) died. The intention‐to‐treat IPTW hazard ratio (HR) for injurious falls for amlodipine (vs RAASi) use was 0.85 (95% confidence interval (CI) 0.66–1.08) and for thiazides (vs RAASi) was 1.22 (95% CI 0.88–1.66). The rates of MACE were similar between those taking anti‐hypertensive medications. Thiazides were discontinued more often than other classes; however, inferences were largely unchanged in as‐treated analyses. Subgroup analyses were generally consistent. Conclusions: Older adults with limited life expectancy experience similar rates of injurious falls and short‐term cardiovascular events after initiating any of the first‐line antihypertensive medications. [ABSTRACT FROM AUTHOR]

Background: Systemic hypertension (SH) is a common cardiovascular disease in older cats that is treated primarily with the calcium channel blocker amlodipine besylate (AML). The systemic effect of AML on the classical and alterative arms of the renin‐angiotensin‐aldosterone system (RAAS) in cats is incompletely characterized. Hypothesis/Objectives: To determine the effect of AML compared to placebo on circulating RAAS biomarkers in healthy cats using RAAS fingerprinting. Animals: Twenty healthy client‐owned cats. Methods: Cats were administered amlodipine besylate (0.625 mg in toto) or placebo by mouth once daily for 14 days in a crossover design with a 4‐week washout period. Plasma AML concentrations and RAAS biomarker concentrations were measured at multiple timepoints after the final dose in each treatment period. Time‐weighted averages for RAAS biomarkers over 24 hours after dosing were compared between treatment groups using Wilcoxon rank‐sum testing. Results: Compared to placebo, AML treatment was associated with increases in markers of plasma renin concentration (median 44% increase; interquartile range [IQR] 19%‐86%; P =.009), angiotensin I (59% increase; IQR 27‐101%; P =.006), angiotensin II (56% increase; IQR 5‐70%; P =.023), angiotensin IV (42% increase; −19% to 89%; P =.013); and angiotensin 1‐7 (38% increase; IQR 9‐118%; P =.015). Conclusions and Clinical Importance: In healthy cats, administration of AML resulted in nonspecific activation of both classical and alternative RAAS pathways. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) medication may reduce blood pressure (BP). Low BP is associated with worse outcomes but how this association is modified by HF medication has not been studied. We evaluated the association between BP and outcomes according to HF medication dose in HF with reduced ejection fraction (HFrEF). Methods and results: We studied HFrEF patients from the Swedish HF registry (2000–2018). Associations between systolic BP (SBP) and cardiovascular death (CVD) and/or HF hospitalization (HFH) were analysed according to doses of renin–angiotensin system (RAS) inhibitors, beta‐blockers and mineralocorticoid receptor antagonists (MRA). Among 42 040 patients (median age 74.0), lower baseline SBP was associated with higher risk of CVD/HFH (adjusted hazard ratio [HR] per 10 mmHg higher SBP: 0.92, 95% confidence interval [CI] 0.92–0.93), which was less high risk under optimized RAS inhibitor and beta‐blocker doses (10% decrease in event rates per 10 mmHg SBP increase in untreated patients vs. 7% decrease in patients at maximum dose, both adjusted p < 0.02). Among the 13 761 patients with repeated measurements, 9.9% reported a SBP decrease >10 mmHg when HF medication doses were increased, whereas 24.6% reported a SBP decrease >10 mmHg with stable/decreasing doses. Decreasing SBP was associated with higher risk of CVD/HFH in patients with stable (HR 1.10, 95% CI 1.04–1.17) or decreasing (HR 1.29, 95% CI 1.18–1.42) HF medication dose but not in patients with an increase in doses (HR 0.94, 95% CI 0.86–1.02). Conclusions: The association of lower SBP with higher risk of CVD/HFH is attenuated in patients with optimized HF medication. These results suggest that low or declining SBP should not limit HF medication optimization. [ABSTRACT FROM AUTHOR]

Aims: To determine differences in the management of diabetic kidney disease (DKD) relevant to patient sex, ethnicity and socio‐economic group in UK primary care. Methods: A cross‐sectional analysis as of January 1, 2019 was undertaken using the IQVIA Medical Research Data dataset, to determine the proportion of people with DKD managed in accordance with national guidelines, stratified by demographics. Robust Poisson regression models were used to calculate adjusted risk ratios (aRR) adjusting for age, sex, ethnicity and social deprivation. Results: Of the 2.3 million participants, 161,278 had type 1 or 2 diabetes, of which 32,905 had DKD. Of people with DKD, 60% had albumin creatinine ratio (ACR) measured, 64% achieved blood pressure (BP, <140/90 mmHg) target, 58% achieved glycosylated haemoglobin (HbA1c, <58 mmol/mol) target, 68% prescribed renin–angiotensin–aldosterone system (RAAS) inhibitor in the previous year. Compared to men, women were less likely to have creatinine: aRR 0.99 (95% CI 0.98–0.99), ACR: aRR 0.94 (0.92–0.96), BP: aRR 0.98 (0.97–0.99), HbA1c: aRR 0.99 (0.98–0.99) and serum cholesterol: aRR 0.97 (0.96–0.98) measured; achieve BP: aRR 0.95 (0.94–0.98) or total cholesterol (<5 mmol/L) targets: aRR 0.86 (0.84–0.87); or be prescribed RAAS inhibitors: aRR 0.92 (0.90–0.94) or statins: aRR 0.94 (0.92–0.95). Compared to the least deprived areas, people from the most deprived areas were less likely to have BP measurements: aRR 0.98 (0.96–0.99); achieve BP: aRR 0.91 (0.8–0.95) or HbA1c: aRR 0.88 (0.85–0.92) targets, or be prescribed RAAS inhibitors: aRR 0.91 (0.87–0.95). Compared to people of white ethnicity; those of black ethnicity were less likely to be prescribed statins aRR 0.91 (0.85–0.97). Conclusions: There are unmet needs and inequalities in the management of DKD in the UK. Addressing these could reduce the increasing human and societal cost of managing DKD. [ABSTRACT FROM AUTHOR]

Mechanisms underlying hyperoxia‐induced airflow restriction in the pediatric lung disease Bronchopulmonary dysplasia (BPD) are unclear. We hypothesized a role for Renin‐Angiotensin System (RAS) activity in BPD. RAS is comprised of a pro‐developmental pathway consisting of angiotensin converting enzyme‐2 (ACE2) and angiotensin II receptor type 2 (AT2), and a pro‐fibrotic pathway mediated by angiotensin II receptor type 1 (AT1). We investigated associations between neonatal hyperoxia, airflow restriction, and RAS activity in a BPD mouse model. C57 mouse pups were randomized to normoxic (FiO2 = 0.21) or hyperoxic (FiO2 = 0.75) conditions for 15 days (P1–P15). At P15, P20, and P30, we measured airflow restriction using plethysmography and ACE2, AT1, and AT2 mRNA and protein expression via polymerase chain reaction and Western Blot. Hyperoxia increased airflow restriction P15 and P20, decreased ACE2 and AT2 mRNA, decreased AT2 protein, and increased AT1 protein expression. ACE2 mRNA and protein remained suppressed at P20. By P30, airflow restriction and RAS expression did not differ between groups. Hyperoxia caused high airflow restriction, increased pulmonary expression of the pro‐fibrotic RAS pathway, and decreased expression of the pro‐developmental in our BPD mouse model. These associated findings may point to a causal role for RAS in hyperoxia‐induced airflow restriction. [ABSTRACT FROM AUTHOR]

Background: The renin–angiotensin system produces a series of biologically active angiotensin (Ang) peptides. These Ang peptides are the major regulators of blood pressure and Na homeostasis, and play a critical role in maintaining cardiovascular and fluid homeostasis. The concentration of Ang peptides in the body is at trace levels, making their detection and quantification a challenge. In this study, a rapid and sensitive analytical method using mass spectrometry coupled with ultrahigh‐performance liquid chromatography (UHPLC/MS) was developed to simultaneously quantify 14 Ang peptides. Methods: UHPLC/MS was employed to quantify 14 Ang peptides in mouse and human plasma. An HSS T3 column (2.1 × 100 mm, 1.8 μm) with an HSS T3 precolumn and triple‐quadrupole mass spectrometer combined with an electrospray ionization source were utilized. Sample pretreatment involved a one‐step protein precipitation using methanol. The total analysis time was within 7.5 min and the target peptides were detected in positive ion mode and quantified by selected reaction monitoring mode. Results: The method was validated for linearity, detection and quantification limits, precision, stability, recovery and matrix effect. The limits of detection of Ang II, Ang III, Ang‐(1–7), Ang‐(2–7), Ang‐(3–7), Ang‐(1–9), bradykinin, Asn1 and Val5‐Ang II are all less than 1 pg mL−1, indicating high sensitivity. The intra‐day and inter‐day precision was within 15%, and the accuracy was between 85% and 115%. Meanwhile, the sample and reference solution were stable within 48 h, and the recovery and matrix effect met the quantitative requirements. Conclusions: The method is currently reported to allow the largest number of Ang peptide species to be detected at one time. In addition, the proposed method offers a fast and reliable approach for comprehensive analysis of Ang metabolism in biological samples, facilitating research on the physiological and pathological states of cardiovascular, kidney and respiratory diseases. [ABSTRACT FROM AUTHOR]

Background: The renin‐angiotensin system (RAS) has been associated with inflammatory bowel disease (IBD), supporting translational relevance of RAS blockers. Comparability of study design/outcomes is fundamental for data analysis/discussion. Objectives: We aimed at evaluating the heterogeneity among protocols and outcomes to study the effect of angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers in IBD. Methods: This study was performed and reported in accordance with the Cochrane recommendations and PRISMA (PROSPERO‐CRD42022323853). Systematic searches were performed in PubMed, Scopus and Web of Science. Studies that met the inclusion criteria were selected. Quality assessment of the studies was done with the SYRCLES's risk of bias tools for animal studies. Results: Thirty‐five pre‐clinical studies and six clinical studies were included. Chemical induction of colitis was the most used model, but variable doses of the induction agent were reported. All studies reported at least a disease activity index, a macroscopic score, or a histologic assessment, but these scores were methodologically heterogeneous and reported for different characteristics. Great heterogeneity was also found in drug interventions. Inflammatory markers assessed as outcomes were different across studies. Conclusion: Lack of standardization of protocols and outcomes among studies threatens the evidence on how RAS blockers influence IBD outcomes. [ABSTRACT FROM AUTHOR]

In addition to being recognised for involvement in cardiovascular control and hydromineral balance, the renin‐angiotensin system (RAS) has also been associated with the neuroendocrine control of energy balance. One of the main brain sites for angiotensin II (ANG II)/type 1 receptor (AT1R) signalling is the subfornical organ (SFO), a circumventricular organ related to the control of autonomic functions, motivated behaviours and energy metabolism. Thus, we hypothesised that circulating ANG II may act on the SFO AT1R receptors to integrate metabolic and hydromineral balance. We evaluated whether food deprivation can modulate systemic RAS activity and Agrt1a brain expression, and if ANG II/AT1R signalling influences the hypothalamic expression of mRNAs encoding neuropeptides and food and water ingestion in fed and fasted Wistar rats. We found a significant increase in both ANG I and ANG II plasma levels after 24 and 48 h of fasting. Expression of Agrt1a mRNA in the SFO and paraventricular nucleus (PVN) also increased after food deprivation for 48 h. Treatment of fasted rats with low doses of losartan in drinking water attenuated the decrease in glycemia and meal‐associated water intake without changing the expression in PVN or arcuate nucleus of mRNAs encoding selected neuropeptides related to energy homeostasis control. These findings point to a possible role of peripheral ANG II/SFO‐AT1R signalling in the control of refeeding‐induced thirst. On the other hand, intracerebroventricular losartan treatment decreased food and water intake over dark time in fed but not in fasted rats. [ABSTRACT FROM AUTHOR]

Aim: To investigate the potential mechanism of once‐weekly glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) in the treatment of type 2 diabetes mellitus (T2DM) complicated with coronary artery disease (CAD). Methods: We searched both Chinese and English databases for randomized controlled trials related to once‐weekly GLP‐1 RA for T2DM complicated with CAD to verify the safety and efficacy of GLP‐1 RA. The underlying mechanism was analysed by network pharmacology. Results: In total, 13 studies with 35 563 participants were included in the analysis. The pooled analysis found that dulaglutide, exenatide and semaglutide outperformed placebo in cardiovascular outcomes in patients with T2DM, with a significant reduction in the incidence of non‐fatal stroke (p <.00). Levels of cardiovascular risk factors were significantly reduced in the once‐weekly GLP‐1 RA group compared with the conventional treatment group (glycated haemoglobin: p <.00; fasting blood glucose: p <.00; weight: p <.00; systolic blood pressure: p <.00; total cholesterol: p <.00; low‐density lipoprotein cholesterol: p <.00). Network pharmacology results were enriched to the renin‐angiotensin system, and matrix metalloproteinase 2 and renin (REN) may be the key targets. In addition, four key targets of dulaglutide, five key targets of exenatide and two key targets of semaglutide were enriched. Conclusions: Our study suggests that once‐weekly GLP‐1 RA may have a potential protective effect on cardiovascular events in patients with T2DM combined with CAD, possibly through the renin‐angiotensin system. However, further research is needed to confirm these findings and determine cause and effect. [ABSTRACT FROM AUTHOR]

The angiotensin II type 2 receptor (AT2R) exerts vasorelaxant, anti‐inflammatory, and antioxidant properties. In obesity, its activation counterbalances the adverse cardiovascular effects of angiotensin II mediated by the AT1R. Preliminary results indicate that it also promotes brown adipocyte differentiation in vitro. Our hypothesis is that AT2R activation could increase BAT mass and activity in obesity. Five‐week‐old male C57BL/6J mice were fed a standard or a high‐fat (HF) diet for 6 weeks. Half of the animals were treated with compound 21 (C21), a selective AT2R agonist, (1 mg/kg/day) in the drinking water. Electron transport chain (ETC), oxidative phosphorylation, and UCP1 proteins were measured in the interscapular BAT (iBAT) and thoracic perivascular adipose tissue (tPVAT) as well as inflammatory and oxidative parameters. Differentiation and oxygen consumption rate (OCR) in the presence of C21 was tested in brown preadipocytes. In vitro, C21‐differentiated brown adipocytes showed an AT2R‐dependent increase of differentiation markers (Ucp1, Cidea, Pparg) and increased basal and H+ leak‐linked OCR. In vivo, HF‐C21 mice showed increased iBAT mass compared to HF animals. Both their iBAT and tPVAT showed higher protein levels of the ETC protein complexes and UCP1, together with a reduction of inflammatory and oxidative markers. The activation of the AT2R increases BAT mass, mitochondrial activity, and reduces markers of tissue inflammation and oxidative stress in obesity. Therefore, insulin reduction and better vascular responses are achieved. Thus, the activation of the protective arm of the renin–angiotensin system arises as a promising tool in the treatment of obesity. [ABSTRACT FROM AUTHOR]

Aims: Whether aldosterone levels after myocardial infarction (MI) are associated with mid‐ and long‐term left ventricular (LV) remodelling in the era of systematic use of renin–angiotensin system inhibitors is uncertain. We prospectively investigated the relationship between aldosterone levels and mid‐ and long‐term LV remodelling in patients with acute MI. Methods and results: Plasma aldosterone was measured in 119 patients successfully treated by primary percutaneous coronary angioplasty for a first acute ST‐elevation MI (STEMI) 2–4 days after the acute event. LV volumes were assessed by cardiac magnetic resonance (CMR) and transthoracic echocardiography (TTE) in the same timeframe and 6 months later. LV assessment was repeated by TTE 3–9 years after MI (n = 80). The median aldosterone level at baseline was 23.1 [16.8; 33.1] pg/ml. In the multivariable model, higher post‐MI aldosterone concentration was significantly associated with more pronounced increase in LV end‐diastolic volume index (TTE: β ± standard error [SE]: 0.113 ± 0.046, p = 0.015; CMR: β ± SE: 0.098 ± 0.040, p = 0.015) and LV end‐systolic volume index (TTE: β ± SE: 0.083 ± 0.030, p = 0.008; CMR: β ± SE: 0.064 ± 0.032, p = 0.048) at 6‐month follow‐up, regardless of the method of assessment. This result was consistent also in patients with a LV ejection fraction (LVEF) >40%. The association between baseline plasma aldosterone and adverse LV remodelling did not persist at the 3–9‐year follow‐up evaluation. Conclusion: Aldosterone concentration in the acute phase was associated with adverse LV remodelling in the medium term, even in the subgroup of patients with LVEF >40%, suggesting a potential role of the mineralocorticoid system in post‐MI adverse remodelling. Plasma aldosterone was no longer associated with LV remodelling in the long term (NCT01109225). [ABSTRACT FROM AUTHOR]

Background: Frail older adults may be less likely to receive guideline‐directed medical therapy (GDMT)—renin‐angiotensin blockers, beta‐blockers, and mineralocorticoid receptor antagonists—for heart failure with reduced ejection fraction (HFrEF). We aimed to examine the uptake of angiotensin receptor neprilysin inhibitor (ARNI) and GDMT in frail older adults with HFrEF. Methods: Using 2015–2019 Medicare data, we estimated the proportion of beneficiaries with HFrEF receiving ARNI and GDMT each year by frailty status, defined by a claims‐based frailty index. Logistic regression was used to identify clinical characteristics associated with ARNI initiation. Cox proportional hazards regression was used to examine the association of GDMT use in 2015 and death or heart failure hospitalization in 2016–2019. Results: Among 147,506–180,386 beneficiaries with HFrEF (mean age: 77 years; 27% women; 42.6–49.1% frail) in 2015–2019, the proportion of patients receiving ARNI increased in both non‐frail (0.4%–16.4%) and frail (0.3%–13.7%) patients (p for yearly‐trend‐by‐frailty = 0.970). Among those not receiving a renin‐angiotensin system blocker, patients with age ≥ 85 years (odds ratio [95% CI], 0.89 [0.80–0.99]), dementia (0.88 [0.81–0.96]), and frailty (0.87 [0.81–0.94]) were less likely to initiate ARNI. The proportion of patients receiving all 3 GDMT classes increased in non‐frail patients (22.0%–27.0%) but changed minimally in frail patients (19.6%–21.8%). Regardless of frailty status, treatment with at least 1 class of GDMT was associated with lower death or heart failure hospitalization than no GDMT medications (hazard ratio [95% CI], 0.94 [0.91–0.97], 0.92 [0.89–0.94], 0.94 [0.91–0.97] for 1, 2, and 3 classes, respectively). Conclusions: Our results suggest an evidence‐practice gap in the use of ARNI and GDMT in Medicare beneficiaries with HFrEF, particularly those with frailty. Efforts to narrow this gap are needed to reduce the burden of HFrEF in older adults. [ABSTRACT FROM AUTHOR]

Background: Angiotensin‐converting enzyme (ACE) and ACE2 are two major enzymes of the renin–angiotensin–aldosterone system (RAAS), which control the formation/degradation of angiotensin (Ang) II and Ang1‐7, regulating their opposite effects. We aimed at evaluating the catalytic activity of ACE and ACE2 in the intestinal content and corresponding intestinal tissue along the gut of Wistar Han rats. Methods: Portions of the ileum, cecum, proximal colon, and distal colon, and the corresponding intestinal content were collected from Wistar Han rats. Enzyme activity was evaluated by fluorometric assays using different substrates: Hippuryl‐His‐Leu for ACE‐C‐domain, Z‐Phe‐His‐Leu for ACE‐N‐domain, and Mca‐APK(Dnp) for ACE2. ACE and ACE2 concentration was assessed by ELISA. Ratios concerning concentrations and activities were calculated to evaluate the balance of the RAAS. Statistical analysis was performed using Friedman test followed by Dunn's multiple comparisons test or Wilcoxon matched‐pairs test whenever needed. Key Results: ACE and ACE2 are catalytically active in the intestinal content along the rat gut. The ACE N‐domain shows higher activity than the C‐domain both in the intestinal content and in the intestinal tissue. ACE and ACE2 are globally more active in the intestinal content than in the corresponding intestinal tissue. There was a distal‐to‐proximal prevalence of ACE2 over ACE in the intestinal tissue. Conclusions & Inferences: This work is the first to report the presence of catalytically active ACE and ACE2 in the rat intestinal content, supporting future research on the regulatory role of the intestinal RAAS on gut function and a putative link to the microbiome. [ABSTRACT FROM AUTHOR]

The renin‐angiotensin system (RAS) plays essential roles in maintaining peripheral cardiovascular homeostasis, with its potential roles in the brain only being recognized more recently. Angiotensin‐I‐converting enzyme (ACE) is the main component of the RAS, and it has been implicated in various disorders of the brain. ACE and other RAS components, including the related enzyme ACE2, angiotensin peptides and their respective receptors, can participate in the pathological state, as well as with potential to contribute to neuroprotection and/or to complement existing treatments for psychiatric illness. In this narrative review, we aimed to identify the main studies describing the functions of the RAS and ACEs in the brain and their association with brain disorders. These include neurodegenerative disorders such as Parkinson's and Alzheimer's diseases, psychiatric illnesses such as schizophrenia, bipolar disorder, and depression. We also discuss the possible association of a functional polymorphism of the ACE gene with these brain diseases and the relevance of the neuroprotective and anti‐inflammatory properties of ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs). Based on this, we conclude that there is significant potential value to the inclusion of ACEis and/or ARBs as a novel integrated approach for the treatment of various disorders of the brain, and particularly for psychiatric illness. [ABSTRACT FROM AUTHOR]

Aims: To investigate whether a heart failure (HF) hospitalization is associated with initiation/discontinuation of guideline‐directed medical HF therapy (GDMT) and consequent outcomes. Methods and results: Among patients in the Swedish HF registry with an ejection fraction <50% enrolled in 2009–2018, initiation/discontinuation of GDMT was investigated by assessing dispensations of GDMT in those with versus without a HF hospitalization. Of 14 737 patients, 6893 (47%) were enrolled when hospitalized for HF. Initiation of GDMT was more likely than discontinuation following a HF hospitalization compared to a control group of patients without a HF hospitalization (odds ratio range 2.1–4.0 vs. 1.4–1.6 for the individual medications), although the proportion of patients not on GDMT was still high (8.1–44.0%). Key patient characteristics triggering less use of GDMT (i.e. less initiation or more discontinuation) were older age and worse renal function. Following a HF hospitalization, initiation of renin–angiotensin system inhibitors/angiotensin receptor–neprilysin inhibitors or beta‐blockers was associated with lower and their discontinuation with higher mortality risk, but no association with mortality was observed for initiation/discontinuation of mineralocorticoid receptor antagonists. Conclusions: Following a HF hospitalization, initiation of GDMT was more likely than discontinuation, although still limited. Perceived or actual low tolerance were barriers to GDMT implementation. Early re‐/initiation of GDMT was associated with better survival. Our findings represent a call for further implementing the current guideline recommendation for an early re‐/initiation of GDMT following a HF hospitalization. [ABSTRACT FROM AUTHOR]

Aim: The hinotori surgical robot system, a newly launched platform, has already been utilized in several urological robotic surgeries; however, limited information is available in terms of its feasibility and safety in each type of surgery. The objectives of this study were to describe the perioperative outcomes of the first series of six patients who underwent robot‐assisted adrenalectomy (RAA) using hinotori, and compare the outcomes with a similar set of five patients undergoing RAA with the existing system, da Vinci. Methods: This study included a total of 11 consecutive patients with adrenal tumors undergoing RAA between July 2020 and November 2022 at our institution. Comprehensive perioperative outcomes in these patients were retrospectively analyzed. Results: Median age, body mass index (BMI), and tumor diameter in the hinotori group were 48 years, 27.5 kg/m2, and 36 mm, respectively, and four patients were diagnosed with a functioning tumor, consisting of three and one with hypersecretion of cortisol and catecholamine, respectively. All procedures using hinotori were performed via the transperitoneal approach, and could be completed without conversion to open surgery. Median operative time, time using robotic system, the estimated blood loss, and length of hospital stay in this group were 119 min, 58 min, 8 mL, and 7 days, respectively, and no patient experienced major perioperative complications. There were no significant differences in clinical characteristics between the hinotori and da Vinci groups, and no significant differences in the perioperative outcomes were noted between these two groups. Conclusion: Despite being a small case series, this is the first study focusing on RAA using the hinotori surgical robot system, which could be efficaciously performed, resulting in the achievement of perioperative findings comparable with those of the da Vinci system. [ABSTRACT FROM AUTHOR]

Aim: The earlier the onset of proteinuria, the higher the incidence of genetic forms. Therefore, we aimed to analyse the spectrum of monogenic proteinuria in Egyptian children presenting at age <2 years. Methods: The results of 27‐gene panel or whole‐exome sequencing were correlated with phenotype and treatment outcomes in 54 patients from 45 families. Results: Disease‐causing variants were identified in 29/45 (64.4%) families. Mutations often occurred in three podocytopathy genes: NPHS1, NPHS2 and PLCE1 (19 families). Some showed extrarenal manifestations. Additionally, mutations were detected in 10 other genes, including novel variants of OSGEP, SGPL1 and SYNPO2. COL4A variants phenocopied isolated steroid‐resistant nephrotic syndrome (2/29 families, 6.9%). NPHS2 M1L was the single most common genetic finding beyond the age of 3 months (4/18 families, 22.2%). Biopsy results did not correlate with genotypes (n = 30). On renin–angiotensin–aldosterone system antagonists alone, partial and complete remission occurred in 3/24 (12.5%) patients with monogenic proteinuria each, whereas 6.3% (1/16) achieved complete remission on immunosuppression. Conclusion: Genotyping is mandatory to avoid biopsies and immunosuppression when proteinuria presents at age <2 years. Even with such a presentation, COL4A genes should be included. NPHS2 M1L was prevalent in Egyptian children (4 months–2 years) with proteinuria, demonstrating precision diagnostic utility. [ABSTRACT FROM AUTHOR]

Background: The behavior of the comprehensive circulating renin‐angiotensin system (RAS) in dogs with myxomatous mitral valve disease (MMVD) before to the onset of congestive heart failure remains largely unexplored. Hypothesis/Objectives: The classical and alternative RAS activity and aldosterone concentrations will be significantly higher in dogs with American College of Veterinary Internal Medicine (ACVIM) stage B2 MMVD compared to normal dogs and dogs with ACVIM stage B1 MMVD. Animals: One‐hundred seventeen client‐owned dogs (normal = 60; B1 = 31; B2 = 26). Methods: Prospective observational study. Angiotensin peptides (AP) and aldosterone concentrations were measured using liquid chromatography and mass spectrometry. Angiotensin converting enzymes 1 and 2 (ACE, ACE2) and renin activity surrogates were calculated from AP concentrations. Equilibrium dialysis (ED) and immediate protease inhibition (PI) methods of AP quantification were compared in 14 healthy dogs. Results: Core RAS activity and aldosterone concentrations did not differ among the 3 groups. However, the balance between the alternative and classical RAS differed, with dogs with stage B2 MMVD having significantly higher ACE2 activity surrogate (ACE2surr) when compared to normal dogs (adjusted P =.02; ratio of medians for ACE2surr [B2:normal], 1.89; 95% confidence interval [CI]: 1.4‐2.6). The ED and PI methods of AP quantification were highly correlated (AngI, r =.9, P <.0001; AngII, r =.8, P =.001). Conclusions and Clinical Importance: Circulating alternative RAS activity, specifically the surrogate measure of ACE2 activity, was increased in dogs with stage B2 MMVD as compared to normal dogs. Equilibrium dialysis results are analogous to immediate protease inhibition in dogs. [ABSTRACT FROM AUTHOR]

Objective: The clinical practice guideline for primary aldosteronism (PA) places a high value on confirmatory tests to sparing patients with false‐positive results in case detection from undergoing adrenal venous sampling (AVS). However, it is unclear whether multiple types of confirmatory tests are more useful than a single type. To evaluate whether the machine‐learned combination of two confirmatory tests is more useful in predicting subtypes of PA than each test alone. Design: A retrospective cross‐sectional study in referral centres. Patients: This study included 615 patients with PA randomly assigned to the training and test data sets. The participants underwent saline infusion test (SIT) and captopril challenge test (CCT) and were subtyped by AVS (unilateral, n = 99; bilateral, n = 516). Measurements: The area under the curve (AUC) and clinical usefulness using decision curve analysis for the subtype prediction in the test data set. Results: The AUCs for the combination of SIT and CCT, SIT alone and CCT alone were 0.850, 0.813 and 0.786, respectively, with no significant differences between them. The AUC for the baseline clinical characteristics alone was 0.872, whereas the AUCs for these combined with SIT, combined with CCT and combined with both SIT and CCT were 0.868, 0.854 and 0.855, respectively, with no significant improvement in AUC. The additional clinical usefulness of the second confirmatory test was unremarkable on decision curve analysis. Conclusions: Our data suggest that patients with positive case detection undergo one confirmatory test to determine the indication for AVS. [ABSTRACT FROM AUTHOR]

Objectives: Human physiology and epidemiology studies have demonstrated complex interactions between the renin–angiotensin–aldosterone system, parathyroid hormone and calcium homeostasis. Several of these studies have suggested that aldosterone inhibition may lower parathyroid hormone (PTH) levels. The objective of this study was to assess the effect of 4 weeks of maximally tolerated mineralocorticoid receptor antagonist therapy with eplerenone on PTH levels in patients with primary hyperparathyroidism (P‐HPT) when compared to amiloride and placebo. We also investigated the synergistic effect of these interventions when combined with cinacalcet for an additional 2 weeks. Design: Randomized, double‐blinded, three parallel‐group, placebo‐controlled trial. Patients: Patients with P‐HPT. Results: Most patients were women (83%) and White (76%). Maximally tolerated doses of eplerenone and amiloride induced significant reductions in blood pressure and increases in renin and aldosterone production; however, despite these physiologic changes, neither intervention induced significant changes in PTH or calcium levels when compared to the placebo. Both eplerenone and amiloride therapy induced significant reductions in procollagen type 1 N‐terminal propeptide levels when compared to placebo. When cinacalcet therapy was added, PTH and calcium levels were markedly reduced in all groups; however, there was no significant difference in PTH or serum calcium reductions between groups. Conclusions: Although maximally tolerated therapy with eplerenone and amiloride induced expected changes in renin, aldosterone and blood pressure, there were no meaningful changes in PTH or serum calcium levels in P‐HPT patients. These results suggest that inhibition of aldosterone action does not have a clinically meaningful role in medical therapy for P‐HPT. [ABSTRACT FROM AUTHOR]

Objective: To test the association between vertical integration of primary care providers (PCPs) and adherence rates for anti‐diabetics, renin angiotensin system antagonists (RASA), and statins. Data Sources: Medicare Part B outpatient fee‐for‐service claims and Medicare Part D event data from 2014 to 2017. Study Design: We estimated difference‐in‐differences regressions, comparing changes in adherence among patients with PCPs who converted from independent to integrated to changes among patients whose PCPs remained independent or integrated during the study period. To test for heterogenous impacts by patient demographics, we estimated triple difference regressions that included additional interaction terms by comorbidity rates, age group, and race/ethnicity. Extraction Methods: We extracted Medicare claims for adults with continuous enrollment in Parts B and D during the study period. Principal Findings: The proportion of patients who had a vertically integrated PCP increased by approximately 23% over the study period. Changes in adherence did not differ significantly between patients based on whether their PCP became integrated (Statins: 0.18, 95% CI −0.13, 0.49; RASA: −0.13, 95% CI −0.46, 0.19; Anti‐Diabetics: −0.20, 95% CI −0.78, 0.38). Among patients with PCPs who became integrated, there were significant decreases in adherence for patients who were Black, Asian, Hispanic, or Native American, above 80 years old, and had greater comorbidities for all three classes. Conclusions: While there were no average changes in adherence following vertical integration of PCPs, health equity worsened, with significant declines in adherence for Black, Asian, Hispanic, and Native American patients, patients over 80 years old, and patients with greater comorbidities. These findings suggest that integration may reduce clinicians' incentives to compete based on the quality of care delivered. Given the price increases associated with integration, integration may be a net welfare loss. [ABSTRACT FROM AUTHOR]

There is growing interest in developing causal inference methods for multi‐valued treatments with a focus on pairwise average treatment effects. Here we focus on a clinically important, yet less‐studied estimand: causal drug‐drug interactions (DDIs), which quantifies the degree to which the causal effect of drug A is altered by the presence versus the absence of drug B. Confounding adjustment when studying the effects of DDIs can be accomplished via inverse probability of treatment weighting (IPTW), a standard approach originally developed for binary treatments and later generalized to multi‐valued treatments. However, this approach generally results in biased results when the propensity score model is misspecified. Motivated by the need for more robust techniques, we propose two empirical likelihood‐based weighting approaches that allow for specifying a set of propensity score models, with the second method balancing user‐specified covariates directly, by incorporating additional, nonparametric constraints. The resulting estimators from both methods are consistent when the postulated set of propensity score models contains a correct one; this property has been termed multiple robustness. In this paper, we derive two multiply‐robust estimators of the causal DDI, and develop inference procedures. We then evaluate their finite sample performance through simulation. The results demonstrate that the proposed estimators outperform the standard IPTW method in terms of both robustness and efficiency. Finally, we apply the proposed methods to evaluate the impact of renin‐angiotensin system inhibitors (RAS‐I) on the comparative nephrotoxicity of nonsteroidal anti‐inflammatory drugs (NSAID) and opioids, using data derived from electronic medical records from a large multi‐hospital health system. [ABSTRACT FROM AUTHOR]

Mutations of rat sarcoma virus (RAS) oncogenes (HRAS, KRAS and NRAS) can contribute to the development of cancers and genetic disorders (RASopathies). The spatiotemporal organization of RAS is an important property that warrants further investigation. In order to function, wild‐type or oncogenic mutants of RAS must be localized to the inner leaflet of the plasma membrane (PM), which is driven by interactions between their C‐terminal membrane‐anchoring domains and PM lipids. The isoform‐specific RAS–lipid interactions promote the formation of nanoclusters on the PM. As main sites for effector recruitment, these nanoclusters are biologically important. Since the spatial distribution of lipids is sensitive to changing environments, such as mechanical and electrical perturbations, RAS nanoclusters act as transducers to convert external stimuli to intracellular mitogenic signalling. As such, effective inhibition of RAS oncogenesis requires consideration of the complex interplay between RAS nanoclusters and various cell surface and extracellular stimuli. In this review, we discuss in detail how, by sorting specific lipids in the PM, RAS nanoclusters act as transducers to convert external stimuli into intracellular signalling. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy, phase III study, randomized trial, type 2 diabetes Keywords: diabetic retinopathy; phase III study; randomized trial; type 2 diabetes EN diabetic retinopathy phase III study randomized trial type 2 diabetes 894 898 5 02/03/23 20230301 NES 230301 BACKGROUND/CONTEXT Diabetic retinopathy (DR) and chronic kidney disease (CKD) are two major forms of microvascular complications in patients with type 1 diabetes and type 2 diabetes (T2D), with shared risk factors (such as poor glycaemic control, smoking, hypertension and dyslipidaemia) and clinical manifestations (microvascular lesions).[1] The steroid hormone aldosterone, which binds to mineralocorticoid receptors, promotes vascular pathology in the retina relevant to the development of DR[2]; antagonism of the retinal mineralocorticoid receptor-aldosterone system may delay progression.[3] Finerenone, a potent and selective, orally administered, non-steroidal mineralocorticoid receptor antagonist (MRA), slowed progression of CKD and reduced the risk of cardiovascular outcomes versus placebo in patients with CKD and T2D in the FIDELIO-DKD (NCT02540993; n = 5674) and FIGARO-DKD (NCT02545049; n = 7352) randomized phase 3 trials.[[4]] In total, 2657 (46.8%) patients in FIDELIO-DKD and 2265 (30.8%) in FIGARO-DKD had DR at baseline.[[6]] No further details on DR were collected in these studies. Effect of finerenone on the occurrence of vision-threatening complications in patients with non-proliferative diabetic retinopathy: Pooled analysis of two studies using routine ophthalmological examinations from clinical trial participants (ReFineDR/DeFineDR) Diabetic retinopathy is a prognostic factor for progression of chronic kidney disease in the patients with type 2 diabetes mellitus. [Extracted from the article]

Background: The role of ERG‐status molecular subtyping in prognosis of prostate cancer (PCa) is still under debate. In this study, we identified differentially expressed genes (DEGs) according to ERG‐status to explore their enriched pathways and implications in prognosis in Hispanic/Latino PCa patients. Methods: RNA from 78 Hispanic PCa tissues from radical prostatectomies (RP) were used for RNA‐sequencing. ERGhigh/ERGlow tumor groups were determined based on the 1.5‐fold change median expression in non‐tumor samples. DEGs with a False Discovery Rate (FDR) < 0.01 and a fold change >2 were identified between ERGhigh and ERGlow tumors and submitted to enrichment analysis in MetaCore. Survival and association analyses were performed to evaluate biochemical recurrence (BCR)‐free survival. Results: The identification of 150 DEGs between ERGhigh and ERGlow tumors revealed clustering of most of the non‐BCR cases (60%) into de ERGhigh group and most of the BCR cases (60.8%) in ERGlow group. Kaplan–Meier survival curves showed a worst BCR‐free survival for ERGlow patients, and a significant reduced risk of BCR was observed for ERGhigh cases (OR = 0.29 (95%CI, 0.10–0.8)). Enrichment pathway analysis identified metabolic‐related pathways, such as the renin‐angiotensin system and angiotensin maturation system, the linoleic acid metabolism, and polyamines metabolism in these ERG groups. Conclusions: ERGlow tumor cases were associated with poor BCR‐free survival in our Hispanic/Latino patients, with metabolism‐related pathways altered in the BCR progression. Impact: Our findings suggest the need to dissect the role of diet, metabolism, and lifestyle as risk factors for more aggressive PCa subtypes. [ABSTRACT FROM AUTHOR]

Background: Despite the availability of extensive literature on the effect of angiotensin‐converting enzyme inhibitors (ACEIs)/angiotensin‐receptor blockers (ARBs) on COVID‐19 outcomes, the evidence is still controversial. We aimed to provide a comprehensive assessment of the effect of ACEIs/ARBs on COVID‐19‐related outcomes by summarising the currently available evidence. Methods: An umbrella review was conducted using Medline (OVID), Embase, Scopus, Cochrane library and medRxiv from inception to 1 February 2021. Systematic reviews with meta‐analysis that evaluated the effect of ACEIs/ARBs on COVID‐19‐related clinical outcomes were eligible. Studies' quality was appraised using the AMSTAR 2 Critical Appraisal Tool. Data were analysed using the random‐effects modelling including several subgroup analyses. Heterogenicity was assessed using I2 statistic. The study protocol was registered in PROSPERO (CRD42021233398) and reported using PRISMA guidelines. Results: Overall, 47 reviews were eligible for inclusion. Out of the nine COVID‐19 outcomes evaluated, there was significant associations between ACEIs/ARBs use and each of death (OR = 0.80, 95%CI = 0.75–0.86; I2 = 51.9%), death/ICU admission as composite outcome (OR = 0.86, 95%CI = 0.80–0.92; I2 = 43.9%), severe COVID‐19 (OR = 0.86, 95%CI = 0.78–0.95; I2 = 68%) and hospitalisation (OR = 1.23, 95%CI = 1.04–1.46; I2 = 76.4%). The significant reduction in death/ICU admission, however, was higher among studies which presented adjusted measure of effects (OR = 0.63, 95%CI = 0.47–0.84) and were of moderate quality (OR = 0.74, 95%CI = 0.63–0.85). Conclusions: Collective evidence from observational studies indicate a good quality evidence on the significant association between ACEIs/ARBs use and reduction in death and death/ICU admission, but poor‐quality evidence on both reducing severe COVID‐19 and increasing hospitalisation. Our findings further support the current recommendations of not discontinuing ACEIs/ARBs therapy in patients with COVID‐19. [ABSTRACT FROM AUTHOR]

However, these hypothesis-generating data provided the rationale for the design of randomized trials aiming to directly compare the combination of SGLT-2 inhibitor plus MRA therapy versus either treatment alone. Albuminuria-lowering effect of dapagliflozin, eplerenone, and their combination in patients with chronic kidney disease: a randomized crossover clinical trial. Keywords: cardiorenal protection; diabetic kidney disease; finerenone; inhibitors; SGLT-2 EN cardiorenal protection diabetic kidney disease finerenone inhibitors SGLT-2 1 5 5 01/27/23 20230201 NES 230201 NOVEL THERAPIES IN DIABETIC KIDNEY DISEASE: SGLT-2 INHIBITORS AND FINERENONE Chronic kidney disease (CKD) is a common comorbidity in type 2 diabetes (T2D), with ~30%-50% of adults with T2D manifesting also persistently elevated albuminuria >30 mg/g, sustained decrease in estimated glomerular filtration rate (eGFR) to levels <60 ml/min/1.73m SP 2 sp or both.[1] The presence and severity of CKD in patients with T2D substantially modify the overall risk of progression to kidney failure, adverse cardiovascular events and all-cause mortality.[2] For almost two decades, the only guideline-directed pharmacological interventions to slow the progression of diabetic kidney disease (DKD) included the adequate glycemic and blood pressure control, as well as the inhibition of the renin-angiotensin system (RAS).[3] Despite optimal treatment, the residual cardiorenal risk of patients with CKD and T2D remained substantially elevated. [Extracted from the article]

Summary: Obstructive sleep apnea is a chronic, sleep‐related breathing disorder, which is an independent risk factor for cardiovascular disease. The renin–angiotensin–aldosterone system regulates salt and water homeostasis, blood pressure, and cardiovascular remodelling. Elevated aldosterone levels are associated with excess morbidity and mortality. We aimed to analyse the influence and implications of renin–angiotensin–aldosterone system derangement in individuals with and without obstructive sleep apnea. We pooled data from 20 relevant studies involving 2828 participants (1554 with obstructive sleep apnea, 1274 without obstructive sleep apnea). The study outcomes were the levels of renin–angiotensin–aldosterone system hormones, blood pressure and heart rate. Patients with obstructive sleep apnea had higher levels of plasma renin activity (pooled wmd+ 0.25 [95% confidence interval 0.04–0.46], p = 0.0219), plasma aldosterone (pooled wmd+ 30.79 [95% confidence interval 1.05–60.53], p = 0.0424), angiotensin II (pooled wmd+ 5.19 [95% confidence interval 3.11–7.27], p < 0.001), systolic (pooled wmd+ 5.87 [95% confidence interval 1.42–10.32], p = 0.0098) and diastolic (pooled wmd+ 3.40 [95% confidence interval 0.86–5.94], p = 0.0086) blood pressure, and heart rate (pooled wmd+ 3.83 [95% confidence interval 1.57–6.01], p = 0.0009) compared with those without obstructive sleep apnea. The elevation remained significant (except for renin levels) when studies involving patients with resistant hypertension were removed. Sub‐group analysis demonstrated that levels of angiotensin II were significantly higher only among the Asian population with obstructive sleep apnea compared with those without obstructive sleep apnea. Body mass index accounted for less than 10% of the between‐study variance in elevation of the renin–angiotensin–aldosterone system parameters. Patients with obstructive sleep apnea have higher levels of renin–angiotensin–aldosterone system hormones, blood pressure and heart rate compared with those without obstructive sleep apnea, which remains significant even among patients without resistant hypertension. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Are renal functional responses to intrarenal angiotensin 1–7 (Ang (1–7)) infusion dependent on the level of the endogenous renin–angiotensin system (RAS) in the two‐kidney one‐clip (2K1C) and deoxycorticosterone acetate (DOCA)‐salt animal models of hypertension?What is the main finding and its importance?The renal actions of Ang (1–7) are dependent on the relative endogenous levels of each arm of the classical angiotensin II–angiotensin II type 1 receptor (AT1R) axis and those of the Ang (1–7)–Mas receptor axis. These findings support the hypothesis that a balance exists between the intrarenal classical and novel arms of the RAS, and in particular the relative abundance of AT1R to Mas receptor, which may to a large extent determine the renal excretory response to Ang (1–7) infusion. This study investigated the action of angiotensin 1–7 (Ang (1–7)) on renal haemodynamic and excretory function in the two‐kidney one‐clip (2K1C) and deoxycorticosterone acetate (DOCA)‐salt rat models of hypertension, in which the endogenous renin–angiotensin system (RAS) activity was likely to be raised or lowered, respectively. Rats were anaesthetised and prepared for the measurement of mean arterial pressure and kidney function during renal interstitial infusion of Ang (1–7) or saline. Kidney tissue concentrations of angiotensin II (Ang II) and Ang (1–7) were determined. Intrarenal infusion of Ang (1–7) into the clipped kidney of 2K1C rats increased urine flow (UV), absolute (UNaV) and fractional sodium (FENa) excretions by 110%, 214% and 147%, respectively. Renal Ang II concentrations of the clipped kidney were increased with no major changes in Ang (1–7) concentration. By contrast, Ang (1–7) infusion decreased UV, UNaV, and FENa by 27%, 24% and 21%, respectively in the non‐clipped kidney in which tissue Ang (1–7) concentrations were increased, but renal Ang II concentrations were unchanged compared to sham animals. Ang (1–7) infusion in DOCA‐salt rats had minimal effects on glomerular filtration rate but significantly decreased UV, UNaV and FENa by ∼30%. Renal Ang (1–7) concentrations were higher and Ang II concentrations were lower in DOCA‐salt rats compared to sham rats. These findings demonstrate that the intrarenal infusion of exogenous Ang (1–7) elicits different renal excretory responses the magnitude of which is dependent on the balance between the endogenous renal Ang II–AT1 receptor axis and Ang (1–7)–Mas receptor axis. [ABSTRACT FROM AUTHOR]

The burden of chronic kidney disease is increasing worldwide, largely due to the increasing global prevalence of diabetes mellitus and hypertension. While renin angiotensin system inhibitors and sodium‐glucose cotransporter two inhibitors are the management cornerstone for reducing kidney and cardiovascular complications in patients with diabetic and non‐diabetic kidney disease (DKD), they are partially effective and further treatments are needed to prevent the progression to kidney failure. Endothelin receptor antagonism represent a potential additional therapeutic option due to its beneficial effect on pathophysiological processes involved in progressive kidney disease including proteinuria, which are independently associated with progression of kidney disease. This review discusses the biological mechanisms of endothelin receptor antagonists (ERA) in kidney protection, the efficacy and safety of ERA in randomised controlled trials reporting on kidney outcomes, and its potential future use in both diabetic and non‐DKDs. Summary at a Glance: This review will provide an detailed review of the biological mechanisms of endothelin receptor antagonists (ERA) in kidney protection, the efficacy and safety of ERA in randomised controlled trials reporting on kidney outcomes, and its potential therapeutic role especially in non‐diabetic chronic kidney diseases. [ABSTRACT FROM AUTHOR]

Aims: To explore the modifying effect of glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) use on outcomes with finerenone across a wide spectrum of patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the pooled analysis of FIDELIO‐DKD and FIGARO‐DKD. Materials and methods: Patients with T2D and CKD treated with optimized renin‐angiotensin system blockade were randomized to finerenone or placebo. Effects of finerenone on a cardiovascular composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and a kidney composite outcome (kidney failure, sustained ≥57% estimated glomerular filtration rate [eGFR] decline, or renal death), change in urine albumin‐to‐creatinine ratio (UACR), and safety were analysed by GLP‐1RA use. Results: Of 13 026 patients, 944 (7.2%) used GLP‐1RAs at baseline. Finerenone reduced the risk of the cardiovascular composite outcome (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.52–1.11 with GLP‐1RA; HR 0.87, 95% CI 0.79–0.96 without GLP‐1RA; P‐interaction = 0.63) and the kidney composite outcome (HR 0.82, 95% CI 0.45–1.48 with GLP‐1RA; HR 0.77, 95% CI 0.67–0.89 without GLP‐1RA; P‐interaction = 0.79) irrespective of baseline GLP‐1RA use. Reduction in UACR with finerenone at Month 4 was –38% in patients with baseline GLP‐1RA use compared with –31% in those without GLP‐1RA use (P‐interaction = 0.03). Overall safety and incidence of hyperkalaemia were similar, irrespective of GLP‐1RA use. Conclusions: The cardiorenal benefits of finerenone on composite cardiovascular and kidney outcomes and UACR reduction in patients with CKD and T2D appear to be maintained, regardless of GLP‐1RA use. Subsequent studies are needed to investigate any potential benefit of this combination. [ABSTRACT FROM AUTHOR]

The present work argues for the involvement of the zinc chelating ability of some non‐steroidal anti‐inflammatory drugs as an additive mechanism able to increase their efficacy against COVID‐19. [ABSTRACT FROM AUTHOR]

Aim: The kaliuretic action of the renin–angiotensin–aldosterone system (RAAS) is well established as highlighted by hyperkalemia side effect of RAAS inhibitors but such action is usually ascribed to systemic RAAS. The present study addresses the involvement of intrarenal RAAS in K+ homeostasis with emphasis on locally generated renin within the collecting duct (CD). Methods: Wild‐type (Floxed) and CD‐specific deletion of renin (CD renin KO) mice were treated for 7 days with a high K+ (HK) diet to investigate the role of CD renin in kaliuresis regulation and further define the underlying mechanism with emphasis on analysis of intrarenal aldosterone biosynthesis. Results: In floxed mice, renin levels were elevated in the renal medulla and urine following a 1‐week HK diet, indicating activation of the intrarenal renin. CD renin KO mice had blunted HK‐induced intrarenal renin response and developed impaired kaliuresis and elevated plasma K+ level (4.45 ± 0.14 vs. 3.89 ± 0.04 mM, p < 0.01). In parallel, HK‐induced intrarenal aldosterone and CYP11B2 expression along with expression of renal outer medullary K+ channel (ROMK), calcium‐activated potassium channel subunit alpha‐1 (α‐BK), α‐Na+‐K+‐ATPase, and epithelial sodium channel (β‐ENaC and cleaved‐γ‐ENaC) expression were all significantly blunted in CD renin KO mice in contrast to the unaltered responses of plasma aldosterone and adrenal CYP11B2. Conclusion: Taken together, these results support a kaliuretic action of CD renin during HK intake. [ABSTRACT FROM AUTHOR]

Uric acid has promoted renal fibrosis and inflammation in experimental studies, but some studies have shown nephroprotective effects due to alleviated oxidative stress. We studied the influence of experimental hyperuricaemia in surgically 5/6 nephrectomized rats. Three weeks after subtotal nephrectomy or sham operation, the rats were allocated to control diet or 2.0% oxonic acid (uricase inhibitor) diet for 9 weeks. Then blood, urine and tissue samples were taken, and renal morphology and oxidative stress were examined. Inflammation and fibrosis were evaluated using immunohistochemistry and real‐time PCR (RT‐PCR). Remnant kidney rats ingesting normal or oxonic acid diet presented with ~60% reduction of creatinine clearance and suppressed plasma renin activity. Oxonic acid diet increased plasma uric acid levels by >80 μmol/L. In remnant kidney rats, moderate hyperuricaemia decreased glomerulosclerosis, tubulointerstitial damage and kidney mast cell count, without influencing the fibrosis marker collagen I messenger RNA (mRNA) content. In both sham‐operated and 5/6 nephrectomized rats, the mast cell product 11‐epi‐prostaglandin‐F2α excretion to the urine and kidney tissue cyclooxygenase‐2 (COX‐2) levels were decreased. To conclude, hyperuricaemic remnant kidney rats displayed improved kidney morphology and reduced markers of oxidative stress and inflammation. Thus, moderately elevated plasma uric acid had beneficial effects on the kidney in this low‐renin model of experimental renal insufficiency. [ABSTRACT FROM AUTHOR]

Background: Sex differences in clinical outcomes have been observed for patients with type 2 diabetes mellitus (T2DM). These could be related to sex disparities in treatment. Objectives: To determine whether there are sex disparities in medication prescribing amongst patients with T2DM. Methods: A cohort study was conducted using the Groningen Initiative to ANalyze Type 2 diabetes Treatment (GIANTT) database, which includes data from primary care patients with T2DM from the north of the Netherlands. Data on demographics, physical examinations, laboratory measurements and prescribing were extracted. A set of validated prescribing quality indicators assessing the prevalence, start, intensification and safety of glucose‐, lipid‐, blood pressure‐ and albuminuria‐lowering medication was applied for the calendar year 2019. Univariate logistic regression analyses were conducted. Results: We included 10,456 patients (47% females). Females were less often treated with metformin (81.7% vs. 86.5%; OR 0.70, 95% CI 0.61–0.80), and were less often prescribed a renin‐angiotensin‐aldosterone inhibitor (RAAS‐i) when treated with multiple blood pressure‐lowering medicines (81.9% vs. 89.3%; OR 0.55, 95% CI 0.46–0.64) or when having albuminuria (74.7% vs. 82.1%; OR 0.64, 95% CI 0.49–0.85) than males. Statin treatment was less frequently started (19.7% vs. 24.7%; OR 0.75, 95% CI 0.58–0.96) and prescribed (58.7% vs. 63.9%; OR 0.80, 95% CI 0.73–0.89) in females. There were no differences in starting and intensifying glucose‐, blood pressure‐ and albuminuria‐lowering medication. Conclusions: Sex disparities in medication prescribing amongst T2DM patients were seen, including less starting with statins and potential undertreatment with RAAS‐i in females. Such disparities may partly explain higher excess risks for cardiovascular and renal complications associated with diabetes observed in females. [ABSTRACT FROM AUTHOR]

Background: Estrogen modulates the renin‐angiotensin‐aldosterone system (RAAS) in women, but sex differences have not been fully explored in dogs. Objective: We hypothesized that the RAAS profile of intact female (IF) Doberman Pinschers (DP) would differ from spayed female (SF) and intact male (IM) DP. Animals: Eighteen healthy DP (6 IF, 6 SF, 6 IM). Methods: Absolute and indexed RAAS metabolites, angiotensin‐converting enzyme (ACE) and ACE2 activities, and genotypes (pyruvate kinase dehydrogenase 4, titin, and ACE variants) were compared among sex groups using Kruskal‐Wallis or chi‐square tests, and linear regression controlling for age. Data are expressed as median (minimum, maximum) and P <.05 was considered significant. Results: The ACE activity was higher in IF DP (656 pmol/L; 436, 784) compared to SF DP (411 pmol/L; 287, 451; P =.01) and IM DP (365 pmol/L; 276, 1200; P =.04) after controlling for age. Angiotensin II, angiotensin I, and plasma renin activity marker (PRA‐S) were higher in IF DP compared to SF DP, but not significantly (P ≤.25). After controlling for age, angiotensin 1‐7/angiotensin I was lower in IF DP compared to SF DP (P =.01). Genotypes did not differ among groups. Most DP (94%) were ACE variant positive. Conclusions and Clinical Significance: Sex and reproductive status influenced the RAAS of DP, with IF DP showing genotype‐independent higher ACE activity. These findings hold implications for sterilization practices in female dogs, and support sex and reproductive status as a source of variability in RAAS studies. Additionally, the frequency of the ACE gene variant was very high in this group of DP. [ABSTRACT FROM AUTHOR]

Aim: To provide a detailled analysis of the microvascular burden in patients with diabetes hopitalized for COVD‐19. Materials and Methods: We analysed data from the French CORONADO initiative and the UK Association of British Clinical Diabetologists (ABCD) COVID‐19 audit, two nationwide multicentre studies, and the AMERICADO, a multicentre study conducted in New York area. We assessed the association between risk of all‐cause death during hospital stay and the following microvascular complications in patients with diabetes hospitalized for COVID‐19: diabetic retinopathy and/or diabetic kidney disease and/or history of diabetic foot ulcer. Results: Among 2951 CORONADO, 3387 ABCD COVID‐19 audit and 9327 AMERICADO participants, microvascular diabetic complications status was ascertained for 1314 (44.5%), 1809 (53.4%) and 7367 (79.0%) patients, respectively: 1010, 1059 and 1800, respectively, had ≥1 severe microvascular complication(s) and 304, 750 and 5567, respectively, were free of any complications. The patients with isolated diabetic kidney disease had an increased risk of all‐cause death during hospital stay: odds ratio [OR] 2.53 (95% confidence interval [CI] 1.66‐3.83), OR 1.24 (95% CI 1.00‐1.56) and OR 1.66 (95% CI 1.40‐1.95) in the CORONADO, the ABCD COVID‐19 national audit and the AMERICADO studies, respectively. After adjustment for age, sex, hypertension and cardiovascular disease (CVD), compared to those without microvascular complications, patients with microvascular complications had an increased risk of all‐cause death during hospital stay in the CORONADO, the ABCD COVID‐19 diabetes national audit and the AMERICADO studies: adjusted OR (adjOR) 2.57 (95% CI 1.69‐3.92), adjOR 1.22 (95% CI 1.00‐1.52) and adjOR 1.33 (95% CI 1.15‐1.53), respectively. In meta‐analysis of the three studies, compared to patients free of complications, those with microvascular complications had an unadjusted OR for all‐cause death during hospital stay of 2.05 (95% CI 1.42‐2.97), which decreased to 1.62 (95% CI 1.19‐2.119) after adjustment for age and sex, and to 1.50 (1.12‐2.02) after hypertension and CVD were further added to the model. Conclusion: Microvascular burden is associated with an increased risk of death in patients hospitalized for COVID‐19. [ABSTRACT FROM AUTHOR]

Background and Purpose: Small interfering RNA (siRNA) targeting liver angiotensinogen lowers blood pressure, but its effects in hypertensive diabetes are unknown. Experimental Approach: To address this, TGR (mRen2)27 rats (angiotensin II‐dependent hypertension model) were made diabetic with streptozotocin over 18 weeks and treated with either vehicle, angiotensinogen siRNA, the AT1 antagonist valsartan, the ACE inhibitor captopril, valsartan + siRNA or valsartan + captopril for the final 3 weeks. Mean arterial pressure (MAP) was measured via radiotelemetry. Key Results: MAP before treatment was 153 ± 2 mmHg. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis and podocyte effacement, without a change in glomerular filtration rate. All treatments lowered MAP and cardiac hypertrophy, and the largest drop in MAP was observed with siRNA + valsartan. Treatment with siRNA lowered circulating angiotensinogen by >99%, and the lowest circulating angiotensin II and aldosterone levels occurred in the dual treatment groups. Angiotensinogen siRNA did not affect renal angiotensinogen mRNA expression, confirming its liver‐specificity. Furthermore, only siRNA with or without valsartan lowered renal angiotensin I. All treatments lowered renal angiotensin II and the reduction was largest (>95%) in the siRNA + valsartan group. All treatments identically lowered albuminuria, whereas only siRNA with or without valsartan restored podocyte foot processes and reduced glomerulosclerosis. Conclusion and Implications: Angiotensinogen siRNA exerts renoprotection in diabetic TGR (mRen2)27 rats and this relies, at least in part, on the suppression of renal angiotensin II formation from liver‐derived angiotensinogen. Clinical trials should now address whether this is also beneficial in human diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Iododerma is an uncommon dermatosis caused by excessive iodine exposure and is associated with significant morbidity and mortality. Because of its heterogenous clinical presentation and variable histopathological findings, which depend on the time the skin biopsy is performed, the diagnosis of iododerma is often delayed. We report a rare case of acute iododerma in a woman with end‐stage diabetic nephropathy with antecedent radioiodine contrast exposure, presenting histopathologically as cryptococcoid neutrophilic dermatosis (CND). We underscore important clinicopathological pitfalls to avoid misdiagnosis with similar overlapping entities such as Sweet syndrome, review all published cases of CND and draw novel insights into its associated entities. [ABSTRACT FROM AUTHOR]