Importance of the (Pro)renin Receptor in Activating the Renin-Angiotensin System During Normotensive and Preeclamptic Pregnancies.

PURPOSE OF REVIEW: For a healthy pregnancy to occur, a controlled interplay between the maternal circulating renin-angiotensin-aldosterone system (RAAS), placental renin-angiotensin system (RAS) and intrarenal renin-angiotensin system (iRAS) is necessary. Functionally, both the RAAS and iRAS interact to maintain blood pressure and cardiac output, as well as fluid and electrolyte balance. The placental RAS is important for placental development while also influencing the maternal circulating RAAS and iRAS. This narrative review concentrates on the (pro)renin receptor ((P)RR) and its soluble form (s(P)RR) in the context of the hypertensive pregnancy pathology, preeclampsia. RECENT FINDINGS: The (P)RR and the s(P)RR have become of particular interest as not only can they activate prorenin and renin, thus influencing levels of angiotensin II (Ang II), but s(P)RR has now been shown to directly interact with and stimulate the Angiotensin II type 1 receptor (AT1R). Levels of both placental (P)RR and maternal circulating s(P)RR are elevated in patients with preeclampsia. Furthermore, s(P)RR has been shown to increase blood pressure in non-pregnant and pregnant rats and mice. In preeclamptic pregnancies, which are characterised by maternal hypertension and impaired placental development and function, we propose that there is enhanced secretion of s(P)RR from the placenta into the maternal circulation. Due to its ability to both activate prorenin and act as an AT1R agonist, excess maternal circulating s(P)RR can act on both the maternal vasculature, and the kidney, leading to RAS over-activation. This results in dysregulation of the maternal circulating RAAS and overactivation of the iRAS, contributing to maternal hypertension, renal damage, and secondary changes to neurohumoral regulation of fluid and electrolyte balance, ultimately contributing to the pathophysiology of preeclampsia.

Preeclampsia in the Context of COVID-19: Mechanisms, Pathophysiology, and Clinical Outcomes.

The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to the global COVID-19 pandemic, significantly impacting the health of pregnant women. Obstetric populations, already vulnerable, face increased morbidity and mortality related to COVID-19, aggravated by preexisting comorbidities. Recent studies have shed light on the potential correlation between COVID-19 and preeclampsia (PE), a leading cause of maternal and perinatal morbidity worldwide, emphasizing the significance of exploring the relationship between these two conditions. Here, we review the pathophysiological similarities that PE shares with COVID-19, with a particular focus on severe COVID-19 cases and in PE-like syndrome cases related with SARS-CoV-2 infection. We highlight cellular and molecular mechanistic inter-connectivity between these two conditions, for example, regulation of renin-angiotensin system, tight junction and barrier integrity, and the complement system. Finally, we discuss how COVID-19 pandemic dynamics, including the emergence of variants and vaccination efforts, has shaped the clinical scenario and influenced the severity and management of both COVID-19 and PE. Continued research on the mechanisms of SARS-CoV-2 infection during pregnancy and the potential risk of developing PE from previous infections is warranted to delineate the complexities of COVID-19 and PE interactions and to improve clinical management of both conditions.

Oat Beta-Glucan Dietary Intervention on Antioxidant Defense Parameters, Inflammatory Response and Angiotensin Signaling in the Testes of Rats with TNBS-Induced Colitis.

Male infertility represents a significant public health concern. There is a negative impact of inflammatory bowel diseases (IBDs) on the male reproductive system. The aim of this study was to investigate whether oat beta-glucan (OBG) with different molar mass can modulate parameters of antioxidant defense and inflammatory response in the testes of adult Sprague-Dawley rats with TNBS-induced colitis and whether the OBG intervention can modulate the inflammatory response in association with the RAS system. Results: higher testicular superoxide dismutase (SOD), glutathione reductase (GR) activities and glutathione (GSH) concentration, and lower testosterone (T) level and glutathione peroxidase (GPx) activity, were observed in rats with colitis than in healthy control ones. TNBS-induced colitis resulted in decreased the angiotensin 1-7 (ANG 1-7) level in the testes of rats fed with low-molar mass OBG compared to control animals. Conclusions: although colitis induced moderate pro-oxidant changes in the gonads, it seems plausible that dietary intervention with different fractions of oat beta-glucans mass may support the maintenance of reproductive homeostasis via the stimulation of the local antioxidant defense system.

Integrated analysis of gut microbiome and its metabolites in ACE2-knockout and ACE2-overexpressed mice.

Background: Aberrant activation of the classic renin-angiotensin system (RAS) and intestinal micro dysbiosis adversely affect insulin resistance (IR), dyslipidemia, and other metabolic syndrome markers. However, the action of angiotensin-converting enzyme 2 (ACE2) and gut health in systemic homeostasis vary, and their interaction is not completely understood. Methods: We adopted a combinatory approach of metabolomics and fecal 16S rRNA analysis to investigate gut microbiota and metabolite in two different mouse models, ACE2 knockout (ACE2 KO) mice and the ACE2-overexpressing obese mice. Results: 16S rRNA gene sequencing revealed that ACE2 influences microbial community composition and function, and ACE2 KO mice had increased Deferribacteres, Alcaligenaceae, Parasutterella, Catenibacterium, and Anaerotruncus, with decreased short-chain fatty acid (SCFA)-producing bacteria (Marvinbryantia and Alistipes). In contrast, ACE2-overexpressed mice exhibited increased anti-inflammatory probiotic (Oscillospiraceae, Marinifilaceae, and Bifidobacteriaceae) and SCFA-producing microbes (Rikenellaceae, Muribaculaceae, Ruminococcaceae, Odoribacter, and Alistipes) and decreased Firmicutes/Bacteroidetes, Lactobacillaceae, Erysipelotrichaceae, and Lachnospiraceae. Metabolome analysis indicated differential metabolites in ACE2 KO and ACE2-overexpression mice, especially the glucolipid metabolism-related compounds. Furthermore, correlation analysis between gut microbiota and metabolites showed a dynamic mutual influence affecting host health. Conclusion: Our study confirms for the first time a significant association between ACE2 status and gut microbiome and metabolome profiles, providing a novel mechanism for the positive effect of ACE2 on energy homeostasis.

Sodium-glucose cotransporter 2 inhibitors and renin-angiotensin-aldosterone system, possible cellular interactions and benefits.

Sodium glucose cotransporter 2 inhibitors (SGLT2is) are a newly developed class of anti-diabetics which exert potent hypoglycemic effects in the diabetic milieu. However, the evidence suggests that they also have extra-glycemic effects. The renin-angiotensin-aldosterone system (RAAS) is a hormonal system widely distributed in the body that is important for water and electrolyte homeostasis as well as renal and cardiovascular function. Therefore, modulating RAAS activity is a main goal in patients, notably diabetic patients, which are at higher risk of complications involving these organ systems. Some studies have suggested that SGLT2is have modulatory effects on RAAS activity in addition to their hypoglycemic effects and, thus, these drugs can be considered as promising therapeutic agents for renal and cardiovascular disorders. However, the exact molecular interactions between SGLT2 inhibition and RAAS activity are not clearly understood. Therefore, in the current study we surveyed the literature for possible molecular mechanisms by which SGLT2is modulate RAAS activity.

Molecular Mechanisms Underlying Vascular Remodeling in Hypertension.

Hypertension, a common cardiovascular disease, is primarily characterized by vascular remodeling. Recent extensive research has led to significant progress in understanding its mechanisms. Traditionally, vascular remodeling has been described as a unidirectional process in which blood vessels undergo adaptive remodeling or maladaptive remodeling. Adaptive remodeling involves an increase in vessel diameter in response to increased blood flow, while maladaptive remodeling refers to the narrowing or thickening of blood vessels in response to pathological conditions. However, recent research has revealed that vascular remodeling is much more complex. It is now understood that vascular remodeling is a dynamic interplay between various cellular and molecular events. This interplay process involves different cell types, including endothelial cells, smooth muscle cells, and immune cells, as well as their interactions with the extracellular matrix. Through these interactions, blood vessels undergo intricate and dynamic changes in structure and function in response to various stimuli. Moreover, vascular remodeling involves various factors and mechanisms such as the renin-angiotensin-aldosterone system (RAS), oxidative stress, inflammation, the extracellular matrix (ECM), sympathetic nervous system (SNS) and mechanical stress that impact the arterial wall. These factors may lead to vascular and circulatory system diseases and are primary causes of long-term increases in systemic vascular resistance in hypertensive patients. Additionally, the presence of stem cells in adventitia, media, and intima of blood vessels plays a crucial role in vascular remodeling and disease development. In the future, research will focus on examining the underlying mechanisms contributing to hypertensive vascular remodeling to develop potential solutions for hypertension treatment. This review provides us with a fresh perspective on hypertension and vascular remodeling, undoubtedly sparking further research efforts aimed at uncovering more potent treatments and enhanced preventive and control measures for this disease.

Real-World Treatment of Hypertension on Hemodialyses Data from a Large Polish Database.

INTRODUCTION: The prevalence of hypertension among patients with end-stage kidney disease (ESKD) undergoing hemodialysis (HD) ranges from 72 to 88% depending on applied diagnostic criteria and the chosen method of blood pressure measurement. Despite the guidelines recommending the widespread use of renin-angiotensin system blockers (RASBs) in patients with kidney disease, their utilization in patients on HD may be suboptimal, especially in patients with preserved diuresis. This hesitance that often steams from concern is often due to fear of a decrease in eGFR and a subsequent decrease in diuresis. The aim of this study was to compare clinical characteristics, blood pressure, safety, and HD adequacy indices in hypertensive HD patients on multiple antihypertensive drug regimens, including diuretic treated with RASB (RASB group) or without RASB (no-RASB) with preserved residual diuresis. We sought to examine the real-life use of RASB in HD patients in relation to their clinical characteristics, blood pressure, safety, and HD adequacy. METHODS: From a database of 5,879 patients receiving HD (mean age 65.2 ± 14.2 years, 60% of males) of the largest provider of HD in the country, we selected the subgroup treated with at least three antihypertensive medications including diuretics. We compared patients treated with RASB to counterparts without RASB (no-RASB). RESULTS: The RASB group has similar age and gender proportions as well as BMI and bioimpedance compared to counterparts. However, dry body mass was significantly lower in the RASB group (78.1 ± 18.3 kg vs. 80.0 ± 18.2 kg, p < 0.017). Prevalence of diabetes mellitus was similar in both groups, but RASB-treated patients have cardiovascular diseases more frequently (70.1 vs. 60.8%; p < 0.001). Systolic blood pressure and the number of antihypertensive drugs used were significantly higher in RASB patients than in counterparts (146 ± 16 mm Hg vs. 144 ± 15 mm Hg; p < 0.001 and 4.1 ± 0.9 vs. 3.5 ± 0.5; p < 0001, respectively). RASB-treated patients have significantly longer dialysis vintage (52.7 ± 44.4 months vs. 40.2 ± 40.9 months; p < 0.001) and dialysis time (722 ± 87.1 min/week vs. 713 ± 93.4 min/week; p < 0.017) than counterparts. Serum potassium was slightly but significantly higher in RASB (5.3 ± 0.8 mmol/L vs. 5.1 ± 0.7 mmol/L; p < 0.01). CONCLUSIONS: In the real world setting, RASB can be safely used in HD patients treated with diuretics with preserved residual diuresis. Given that many HD patients present numerous multimorbidities, RASB should not only be considered as an additional hypotensive drug in poorly controlled hypertension but also in other compelling indications in HD patients. The tendency toward hyperkalemia in HD patients could be effectively managed with appropriate diet and HD prescription adjustments.

Renin-Angiotensin System Inhibition and Cardiac Damage in Patients Undergoing Transcatheter Aortic Valve Replacement.

BACKGROUND: The optimal medical treatment strategy after transcatheter aortic valve replacement (TAVR) has not been established, and may be impacted by the extent of extra-valvular cardiac damage. We aimed to investigate the prognostic effect of renin-angiotensin system (RAS) inhibitors in TAVR patients stratified by the extent of extra-valvular cardiac damage. METHODS: In a prospective TAVR registry, patients were retrospectively evaluated for baseline cardiac damage and classified into five stages of cardiac damage (0-4) according to established criteria. Clinical outcomes at 1 year were compared according to RAS inhibitor prescription at discharge. RESULTS: Among 2,247 eligible patients undergoing TAVR between August 2007 and June 2021, 1,634 (72.7%) were prescribed RAS inhibitors at discharge. Eighty-three patients (3.7%) were classified as Stage 0, 276 (12.3%) as Stage 1, 889 (39.6%) as Stage 2, 489 (21.8%) as Stage 3, and 510 (22.7%) as Stage 4. RAS inhibitor prescription after TAVR was associated with a reduced risk of 1-year mortality (HRadjusted 0.59, 95% CI 0.45-0.77). The protective effect was accentuated among patients with cardiac stage 3 and 4 (HRadjusted 0.54, 95% CI 0.32-0.92 and HRadjusted 0.58, 95% CI 0.36-0.92, respectively), but not statistically significant in stages 2 (HRadjusted 0.70, 95% CI 0.43-1.14). CONCLUSIONS: In patients undergoing TAVR, we found a strong association of RAS inhibitor prescription and improved clinical outcome in the overall population, and there were no signs of heterogeneity across stages of cardiac damage.

Aerobic Exercise in the Aquatic Environment Suppresses the Plasma Renin Activity in Individuals with Type 2 Diabetes: A Secondary Analysis of a Randomized Clinical Trial.

To compare the acute effects of aquatic walking/running versus dry-land walking/running on blood glucose and plasma renin activity (PRA) in individuals with type 2 diabetes, participants with type 2 diabetes performed deep-water or dry-land walking and/or running sessions in a swimming pool or on an athletics track, respectively. Both sessions comprised seven blocks of 3 min at 85-90% of the heart rate deflection point (HRDP), interspersed with 2 min at <85% HRDP, totaling 35 min, with a 48 h interval between sessions. PRA and blood glucose were assessed before and immediately after the sessions. Generalized estimation equations were used to verify the session effects, with the Bonferroni post hoc test, considering the significance level as 0.05. Twelve individuals (53.2 ± 8.9 years) diagnosed with type 2 diabetes for 6.3 ± 6.34 years participated in the study. A reduction in PRA was found only after the aquatic session (-7.75 ng/mL/h; -69%; p: 0.034), while both aquatic and dry-land sessions similarly reduced the blood glucose levels (aquatic: -38 mg/dL, -21%; dry-land: -26 mg/dL, -14%; time effect, p = 0.007). Despite yielding similar glycemic reductions as dry-land walking/running, aquatic walking/running led to an expressive decrease in PRA among individuals with type 2 diabetes.

Current understanding of the link between angiotensin-converting enzyme and pain perception.

The renin-angiotensin system (RAS) is known to affect diverse physiological processes that affect the functioning of many key organs. Angiotensin-converting enzyme (ACE) modulates a variety of bioactive peptides associated with pain. ACE inhibitors (ACEis) have found applications in the treatment of cardiovascular, kidney, neurological and metabolic disorders. However, ACEis also tend to display undesirable effects, resulting in increased pain sensitization and mechanical allodynia. In this review, we provide comprehensive discussion of preclinical and clinical studies involving the evaluation of various clinically approved ACEis. With the emerging knowledge of additional factors involved in RAS signaling and the indistinct pharmacological role of ACE substrates in pain, extensive studies are still required to elucidate the mechanistic role of ACE in pain perception.

Placental ACE2 Expression: A Possible Pathogenetic Mechanism for Infantile Hemangiomas.

ACE2 is a mono-carboxypeptidase with remarkable vasculo-protective properties, and its expression in the human placenta plays a central role in blood pressure homeostasis and fetal perfusion. Therefore, an alteration in the placental expression of ACE2 could be responsible for reduced placental perfusion and infantile hemangioma (IH) development. Study placentae were collected from patients affected by IHs who were referred to our Dermatology Clinic from 2016 to 2022, while control placentae were randomly collected while matching cases for gestational age. Immunohistochemical investigations were performed with a recombinant anti-ACE2 rabbit monoclonal antibody. A total of 47 placentae were examined, including 20 study placentae and 27 control ones. The mean placental weight was significantly lower in the study group (380.6 g vs. 502.3 g; p = 0.005), while subclinical chorioamnionitis occurred more frequently in the study group (20% vs. 0%, p = 0.03). The mean ACE2 expression was dramatically lower in the study group (χ2 = 42.1 p < 0.001), and the mean placental weight was significantly lower when ACE2 was not expressed compared to the 25-75% and >75% classes of expression (p < 0.05). This study demonstrated that ACE2, as a marker for tissue hypoxia, is dramatically hypo-expressed in placentae belonging to mothers who delivered one or more babies with IH compared to the controls.

Aerobic training increases renal antioxidant defence and reduces angiotensin II levels, mitigating the high mortality in SHR-STZ model.

OBJECTVE: The purpose of the research was to investigate the effects of aerobic training on renal function, oxidative stress, intrarenal renin-angiotensin system, and mortality of hypertensive and diabetic (SHR-STZ) rats. MATERIALS AND METHODS: Blood pressure, creatinine, urea levels, urinary glucose, urine volume, and protein excretion were reduced in trained SHR-STZ rats. RESULTS: Aerobic training not only attenuated oxidative stress but also elevated the activity of antioxidant enzymes in the kid'ney of SHR-STZ rats. Training increased intrarenal levels of angiotensin-converting enzymes (ACE and ACE2) as well as the neprilysin (NEP) activity, along with decreased intrarenal angiotensin II (Ang II) levels. Aerobic training significantly improved the survival of STZ-SHR rats. CONCLUSION: The protective role of aerobic training was associated with improvements in the renal antioxidative capacity, reduced urinary protein excretion along with reduced intrarenal Ang II and increased NEP activity. These findings might reflect a better survival under the combined pathological conditions, hypertension, and diabetes.

Efficacy and safety of dual renin-angiotensin system (RAS) blockade for non-elderly diabetic kidney disease patients with preserved eGFR.

AIM: Although sodium glucose cotransporter2 inhibitor (SGLT-2I) is widely used in clinical practice, sufficient renin-angiotensin system (RAS) inhibition remains the cornerstone of diabetic kidney disease (DKD) treatment. The aim of this single-center study was to evaluate the efficacy and safety of dual RAS blockade compared with angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) monotherapy in non-elderly DKD patients with preserved eGFR (WHO Standard, < 60y). METHODS: This single-center study was registered in Chinese Clinical Trial Registry (ChiCTR1900024752), and approved by the ethical committee (KY201994). In this study, we recruited non-elderly type 2 diabetes volunteers with initial diagnosis of DKD to receive dual RAS blockade or monotherapy. 150 non-elderly DKD patients with preserved eGFR were recruited. The patients were randomly divided into dual RAS blockade group and monotherapy group. The dual RAS blockade group treatment regimen was an 80 mg valsartan plus a 4 mg perindopril tert-butylamine per day. At the same time, monotherapy group patients who received the 8 mg perindopril tert-butylamine or 160 mg valsartan monotherapy. The clinical data of the three groups were compared at baseline and collected during the follow-up period of 12 months. RESULTS: The baseline of patients who received dual RAS blockade was similar to that of monotherapy group. After 12 months of treatment, the median level of proteinuria in the dual RAS blockade group was significantly lower than that in the monotherapy group. There was no significant difference in the estimated glomerular filtration rate (eGFR) level, potassium, blood pressure and no serious adverse reactions. CONCLUSIONS: In non-elderly DKD patients with preserved eGFR, dual RAS blockade is superior to control proteinuria, and does not increase the probability of adverse reactions such as hyperkalemia, hypotension and acute kidney injury in 12 months.

The angiotensin II/type 1 angiotensin II receptor pathway is implicated in the dysfunction of albumin endocytosis in renal proximal tubule epithelial cells induced by high glucose levels.

It is well-established that dysfunction of megalin-mediated albumin endocytosis by proximal tubule epithelial cells (PTECs) and the activation of the Renin-Angiotensin System (RAS) play significant roles in the development of Diabetic Kidney Disease (DKD). However, the precise correlation between these factors still requires further investigation. In this study, we aimed to elucidate the potential role of angiotensin II (Ang II), a known effector of RAS, as the mediator of albumin endocytosis dysfunction induced by high glucose (HG) in PTECs. To achieve this, we utilized LLC-PK1 and HK-2 cells, which are well-established in vitro models of PTECs. Using albumin-FITC or DQ-albumin as tracers, we observed that incubation of LLC-PK1 and HK-2 cells with HG (25 mM for 48 h) significantly reduced canonical receptor-mediated albumin endocytosis, primarily due to the decrease in megalin expression. HG increased the concentration of Ang II in the LLC-PK1 cell supernatant, a phenomenon associated with an increase in angiotensin-converting enzyme (ACE) expression and a decrease in prolyl carboxypeptidase (PRCP) expression. ACE type 2 (ACE2) expression remained unchanged. To investigate the potential impact of Ang II on HG effects, the cells were co-incubated with angiotensin receptor inhibitors. Only co-incubation with 10-7 M losartan (an antagonist for type 1 angiotensin receptor, AT1R) attenuated the inhibitory effect of HG on albumin endocytosis, as well as megalin expression. Our findings contribute to understanding the genesis of tubular albuminuria observed in the early stages of DKD, which involves the activation of the Ang II/AT1R axis by HG.

Impact of Renin-Angiotensin System Blockade on Mortality and Allograft Loss among Renal Transplant Recipients: A Systematic Review and Meta-Analysis.

INTRODUCTION: The blockade of the renin-angiotensin system (RAS) has a beneficial effect on reducing the levels of proteinuria and blood pressure in patients with chronic kidney disease (CKD) and reduces the risk of developing end-stage kidney disease in CKD patients. Nonetheless, a debate persists regarding the impact of RAS inhibitors on outcomes such as mortality and graft survival in renal transplant patients. To assess the effect of RAS inhibitors on graft recipients in the past decade, we conducted a systematic review and meta-analysis. METHODS: We searched Embase, PubMed, and the Cochrane Central Register of Clinical Trials from January 1, 2012, to August 1, 2022. We included 14 articles, comprising 5 randomized controlled trials (RCTs) and 9 cohort studies, including 45,377 patients. These studies compared patient or graft survival between an RAS inhibitor treatment arm and a control arm. RESULTS: The meta-analysis revealed that RAS blockade was significantly associated with lower mortality in cohort studies (risk ratio [RR] = 0.66, 95% confidence interval [CI]: 0.55-0.79), reduced allograft loss in cohort studies (RR = 0.62, 95% CI: 0.54-0.71), and significant changes in systolic blood pressure in RCTs. Subgroup analysis of the groups of interest (interventions involving RAS blockade, follow-up period of ≥5 years) showed consistently reduced mortality (RR = 0.67, 95% CI: 0.56-0.81) and reduced allograft loss (RR = 0.61, 95% CI: 0.54-0.70). CONCLUSIONS: Our results demonstrated that the application of RAS blockade among renal transplant recipients was associated with lower mortality and allograft loss in cohort studies but not in RCTs. More powered clinical trials are needed to evaluate the effects of RAS blockade in renal transplant recipients.

The role of ACE2 in RAS axis on microglia activation in Parkinson's disease.

BACKGROUND: The classic renin-angiotensin system (RAS) induces organ damage, while the ACE2/Ang-(1-7)/MasR axis opposes it. However, the role of ACE2 in the brain is unclear. We studied ACE2's role in the brain. METHOD: We used male C57BL/6J (WT) mice, ACE2 knockout (KO) mice, and MPTP-induced mice. Behavioral tests confirmed successful modeling. We assessed the impact of ACE2 KO on the RAS axis and PD index, including ACE, ACE2, AT1, AT2, MasR, TH, α-syn, and Iba1. We investigated ACE2 and MasR's involvement in microglial activation via western blot and immunofluorescence. GSE10867 and GSE26532 datasets were used to analyze the effects of AT1 antagonists and in vitro PD models on microglia. RESULT: Behavioral tests revealed that MPTP mice displayed motor deficits, depression, anxiety, and increased inflammatory markers in the SN and CPU, with reduced antioxidant capacity. ACE2 KO worsened these symptoms and exacerbated inflammation and oxidative stress. LPS-induced ACE2/MasR activation in BV2 cells demonstrated anti-inflammatory and neuroprotective effects by modulating microglial polarization. Antagonists inhibited microglial activation via inflammation and ROS processes. CONCLUSION: The RAS axis regulates inflammation and oxidative stress to maintain CNS function, suggesting potential targets for neurologic disease treatment. Understanding microglial RAS activation can offer new therapeutic strategies.

Progressive Kidney Failure by Angiotensinogen Inactivation in the Germline.

BACKGROUND: Autosomal recessive renal tubular dysgenesis is a rare, usually fatal inherited disorder of the renin-angiotensis system (RAS). Herein, we report an adolescent individual experiencing an unknown chronic kidney disease and aim to provide novel insights into disease mechanisms. METHODS: Exome sequencing for a gene panel associated with renal disease was performed. The RAS was assessed by comprehensive biochemical analysis in blood. Renin expression was determined in primary tubular cells by quantitative polymerase chain reaction and in situ hybridization on kidney biopsy samples. Allele frequencies of heterozygous and biallelic deleterious variants were determined by analysis of the Genomics England 100,000 Genomes Project. RESULTS: The patient was delivered prematurely after oligohydramnios was detected during pregnancy. Postnatally, he recovered from third-degree acute kidney injury but developed chronic kidney disease stage G3b over time. Exome sequencing revealed a previously reported pathogenic homozygous missense variant, p.(Arg375Gln), in the AGT (angiotensinogen) gene. Blood AGT concentrations were low, but plasma renin concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of renin. Angiotensin II and aldosterone in blood were not abnormally elevated. CONCLUSIONS: Renal tubular dysgenesis may present as chronic kidney disease with a variable phenotype, necessitating broad genetic analysis for diagnosis. Functional analysis of the RAS in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of renin in vascular and tubular cells of the kidney and in plasma in response to depletion of AGT substrate as a source of Ang II (similarly observed with hepatic AGT silencing for the treatment of hypertension).

[Renoprotective treatments : renin-angiotensin-aldosterone system blockade and beyond]. / Néphroprotection médicamenteuse : au-delà du blocage du système rénine-angiotensine.

RENOPROTECTIVE TREATMENTS: RENIN-ANGIOTENSINALDOSTERONE SYSTEM BLOCKADE AND BEYOND. Patients with chronic kidney disease (CKD) require both etiological and symptomatic treatments to slow renal function decline. Reductions of protein and salt intakes are required. Pharmacological treatments combines blockade of the renin-angiotensin system, sodium-glucose co-transporter type 2 inhibitors and mineralocorticoid receptor antagonists in most diabetic patients. The albumin creatinine ration (ACR) in morning spot urine samples is now a therapeutic target both in diabetic and non-diabetic CKD patients.

NÉPHROPROTECTION MÉDICAMENTEUSE : AU-DELÀ DU BLOCAGE DU SYSTÈME RÉNINE-ANGIOTENSINE. Au-delà du traitement étiologique éventuel d'une maladie rénale chronique (MRC), et du contrôle de l'ensemble des facteurs de risque vasculaire, un traitement symptomatique est nécessaire pour ralentir le déclin de la fonction rénale. La prise en charge diététique permet de limiter les apports en protéines et en sel. Le traitement pharmacologique comporte nécessairement une association d'un bloqueur du système rénine-angiotensine-aldostérone, le plus souvent un inhibiteur du co-transport sodiumglucose de type 2 (SGLT2i) et chez certains diabétiques un antagoniste des récepteurs des minéralocorticoïdes (ARM). Le rapport albuminurie/créatininurie (RAC) sur un échantillon d'urine devient une cible thérapeutique aussi bien chez les non-diabétiques que chez les diabétiques.