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1.
Int J Mol Sci ; 25(17)2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39273282

RESUMO

Every individual at some point encounters the progressive biological process of aging, which is considered one of the major risk factors for common diseases. The main drivers of aging are oxidative stress, senescence, and reactive oxygen species (ROS). The renin-angiotensin-aldosterone system (RAAS) includes several systematic processes for the regulation of blood pressure, which is caused by an imbalance of electrolytes. During activation of the RAAS, binding of angiotensin II (ANG II) to angiotensin II type 1 receptor (AGTR1) activates intracellular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate superoxide anions and promote uncoupling of endothelial nitric oxide (NO) synthase, which in turn decreases NO availability and increases ROS production. Promoting oxidative stress and DNA damage mediated by ANG II is tightly regulated. Individuals with sodium deficiency-associated diseases such as Gitelman syndrome (GS) and Bartter syndrome (BS) show downregulation of inflammation-related processes and have reduced oxidative stress and ROS. Additionally, the histone deacetylase sirtuin-1 (SIRT1) has a significant impact on the aging process, with reduced activity with age. However, GS/BS patients generally sustain higher levels of sirtuin-1 (SIRT1) activity than age-matched healthy individuals. SIRT1 expression in GS/BS patients tends to be higher than in healthy age-matched individuals; therefore, it can be assumed that there will be a trend towards healthy aging in these patients. In this review, we highlight the importance of the hallmarks of aging, inflammation, and the RAAS system in GS/BS patients and how this might impact healthy aging. We further propose future research directions for studying the etiology of GS/BS at the molecular level using patient-derived renal stem cells and induced pluripotent stem cells.


Assuntos
Envelhecimento , Estresse Oxidativo , Sistema Renina-Angiotensina , Sirtuína 1 , Humanos , Sistema Renina-Angiotensina/fisiologia , Envelhecimento/metabolismo , Sirtuína 1/metabolismo , Sirtuína 1/genética , Espécies Reativas de Oxigênio/metabolismo , Síndrome de Gitelman/metabolismo , Síndrome de Gitelman/genética , Síndrome de Bartter/metabolismo , Síndrome de Bartter/genética , Sódio/metabolismo , Angiotensina II/metabolismo
2.
Int J Mol Sci ; 25(17)2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39273497

RESUMO

The hormone renin is produced in the kidney by the juxtaglomerular cells. It is the rate-limiting factor in the circulating renin-angiotensin-aldosterone system (RAAS), which contributes to electrolyte, water, and blood pressure homeostasis. In the kidneys, the distal tubule and the collecting duct are the key target segments for RAAS. The collecting duct is important for urine production and also for salt, water, and acid-base homeostasis. The critical functional role of the collecting duct is mediated by the principal and the intercalated cells and is regulated by different hormones like aldosterone and vasopressin. The collecting duct is not only a target for hormones but also a place of hormone production. It is accepted that renin is produced in the collecting duct at a low level. Several studies have described that the cells in the collecting duct exhibit plasticity properties because the ratio of principal to intercalated cells can change under specific circumstances. This narrative review focuses on two aspects of the collecting duct that remain somehow aside from mainstream research, namely the cell plasticity and the renin expression. We discuss the link between these collecting duct features, which we see as a promising area for future research given recent findings.


Assuntos
Plasticidade Celular , Túbulos Renais Coletores , Sistema Renina-Angiotensina , Renina , Renina/metabolismo , Humanos , Animais , Túbulos Renais Coletores/metabolismo , Sistema Renina-Angiotensina/fisiologia , Vasopressinas/metabolismo
3.
Ren Fail ; 46(2): 2400541, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39248389

RESUMO

AIMS: Finerenone has been approved for treating diabetic kidney disease (DKD) with reducing cardiorenal risk. Real-world data on finerenone treatment for the management of DKD are presently lacking. This study aimed to investigate the effect of finerenone on the renal parameters of the Chinese DKD population in the real-world medical setting for the first time, especially in combination with renin-angiotensin system inhibitors (RASi) and sodium-glucose cotransporter 2 inhibitors (SGLT2i). METHODS: Forty-two DKD patients were selected and completed a 6-month finerenone treatment. Renal parameters and adverse effects were collected at every visit. RESULTS: The median urine albumin-to-creatinine ratio (UACR) was 1426.11 (755.42, 3638.23) mg/g. Among them, the proportion of patients with a UACR of 300-5000 mg/g was 76.2%, and the proportion of patients with a UACR of >5000 mg/g was 14.3%. The median estimated glomerular filtration rate (eGFR) was 54.50 (34.16, 81.73) mL/min/1.73 m2. Finerenone decreased the UACR significantly throughout the study period (p < .05). The maximal decline of UACR at month 6 was 73%. Moreover, the proportion of patients with a 30% or greater reduction in UACR was 68.42% in month 6. There was a smaller decline (9-11%) in the eGFR after initiating finerenone (p > .05). One patient each discontinued finerenone due to hyperkalemia (2.4%) and acute kidney injury (2.4%). No patient reported hypotension, breast pain, and gynecomastia. CONCLUSIONS: This study from China first demonstrated finerenone decreased UACR with manageable safety in real-world DKD treatment. A triple regimen of RASi, SGLT2i, and finerenone may be a promising treatment strategy for lowering albuminuria and reducing hyperkalemia risk in advanced DKD patients.


Assuntos
Nefropatias Diabéticas , Taxa de Filtração Glomerular , Naftiridinas , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Masculino , Feminino , Nefropatias Diabéticas/tratamento farmacológico , China , Pessoa de Meia-Idade , Idoso , Naftiridinas/uso terapêutico , Naftiridinas/efeitos adversos , Taxa de Filtração Glomerular/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Albuminúria/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Creatinina/sangue , Creatinina/urina , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos , Resultado do Tratamento
4.
Rev Med Suisse ; 20(884): 1488-1491, 2024 Aug 28.
Artigo em Francês | MEDLINE | ID: mdl-39219391

RESUMO

In addition to optimal glycemic control and management of other factors aggravating the pathology (hypertension, dyslipidemia, -obesity), the cornerstone of treatment of diabetic kidney disease (DKD) includes blockers of the renin-angiotensin system, sodium-glucose cotransporter 2 inhibitors or nonsteroidal antagonists of the mineralocorticoid receptor (finerenone). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended in the treatment of high-risk patients with type 2 diabetes (T2DM) to reduce cardiovascular (CV) risk. Data from CV studies indicate a nephroprotective effect of certain GLP-1 RAs in T2DM patients with DKD. The FLOW study published in May 2024, analyzing the impact of semaglutide vs placebo on renal events as primary outcome, confirms this renal protection of GLP-1 RAs.


Outre le contrôle glycémique et la prise en charge d'autres ­facteurs d'aggravation de la pathologie, la pierre angulaire du traitement de la maladie rénale diabétique (MRD) comprend les bloqueurs du système rénine-angiotensine, les inhibiteurs du cotransporteur sodium-glucose de type 2 ou encore la finérénone (antagoniste de l'aldostérone). Les agonistes du récepteur du glucagon-like peptide-1 (ARGLP-1) sont recommandés dans le traitement des patients avec un diabète de type 2 (DT2) à haut risque afin de réduire le risque cardiovasculaire (CV). Les ­données provenant des études CV indiquent un effet néphro­protecteur de certains ARGLP-1 chez les patients DT2 avec MRD. L'étude FLOW, publiée fin mai 2024 et analysant l'impact du sémaglutide sur les événements rénaux comme critère principal, confirme cette protection rénale des ARGLP-1.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Nefropatias Diabéticas/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/farmacologia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Peptídeos Semelhantes ao Glucagon/farmacologia , Doenças Cardiovasculares/prevenção & controle , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon
5.
BMC Genomics ; 25(1): 770, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39118009

RESUMO

The harsh and dry conditions of desert environments have resulted in genomic adaptations, allowing for desert organisms to withstand prolonged drought, extreme temperatures, and limited food resources. Here, we present a comprehensive exploration of gene expression across five tissues (kidney, liver, lung, gastrointestinal tract, and hypothalamus) and 19 phenotypic measurements to explore the whole-organism physiological and genomic response to water deprivation in the desert-adapted cactus mouse (Peromyscus eremicus). The findings encompass the identification of differentially expressed genes and correlative analysis between phenotypes and gene expression patterns across multiple tissues. Specifically, we found robust activation of the vasopressin renin-angiotensin-aldosterone system (RAAS) pathways, whose primary function is to manage water and solute balance. Animals reduced food intake during water deprivation, and upregulation of PCK1 highlights the adaptive response to reduced oral intake via its actions aimed at maintained serum glucose levels. Even with such responses to maintain water balance, hemoconcentration still occurred, prompting a protective downregulation of genes responsible for the production of clotting factors while simultaneously enhancing angiogenesis which is thought to maintain tissue perfusion. In this study, we elucidate the complex mechanisms involved in water balance in the desert-adapted cactus mouse, P. eremicus. By prioritizing a comprehensive analysis of whole-organism physiology and multi-tissue gene expression in a simulated desert environment, we describe the complex response of regulatory processes.


Assuntos
Peromyscus , Privação de Água , Animais , Peromyscus/genética , Peromyscus/fisiologia , Perfilação da Expressão Gênica , Sistema Renina-Angiotensina/genética , Regulação da Expressão Gênica , Transcriptoma , Adaptação Fisiológica/genética , Especificidade de Órgãos/genética , Fenótipo
6.
J Biochem Mol Toxicol ; 38(8): e23795, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39132761

RESUMO

Renal fibrosis (RF) is one of the underlying pathological conditions leading to progressive loss of renal function and end-stage renal disease (ESRD). Over the years, various therapeutic approaches have been explored to combat RF and prevent ESRD. Despite significant advances in understanding the underlying molecular mechanism(s), effective therapeutic interventions for RF are limited. Current therapeutic strategies primarily target these underlying mechanisms to halt or reverse fibrotic progression. Inhibition of transforming growth factor-ß (TGF-ß) signaling, a pivotal mediator of RF has emerged as a central strategy to manage RF. Small molecules, peptides, and monoclonal antibodies that target TGF-ß receptors or downstream effectors have demonstrated potential in preclinical models. Modulating the renin-angiotensin system and targeting the endothelin system also provide established approaches for controlling fibrosis-related hemodynamic changes. Complementary to pharmacological strategies, lifestyle modifications, and dietary interventions contribute to holistic management. This comprehensive review aims to summarize the underlying mechanisms of RF and provide an overview of the therapeutic strategies and novel antifibrotic agents that hold promise in its treatment.


Assuntos
Antifibróticos , Fibrose , Humanos , Fibrose/tratamento farmacológico , Antifibróticos/uso terapêutico , Antifibróticos/farmacologia , Nefropatias/tratamento farmacológico , Nefropatias/patologia , Animais , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/antagonistas & inibidores , Rim/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
7.
Int J Mol Sci ; 25(15)2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39125667

RESUMO

Activation of the renin-angiotensin-aldosterone system (RAAS) plays an important pathophysiological role in hypertension. Increased mRNA levels of the angiotensinogen angiotensin-converting enzyme, angiotensin type 1 receptor gene, Agtr1a, and the aldosterone synthase gene, CYP11B2, have been reported in the heart, blood vessels, and kidneys in salt-sensitive hypertension. However, the mechanism of gene regulation in each component of the RAAS in cardiovascular and renal tissues is unclear. Epigenetic mechanisms, which are important for regulating gene expression, include DNA methylation, histone post-translational modifications, and microRNA (miRNA) regulation. A close association exists between low DNA methylation at CEBP-binding sites and increased AGT expression in visceral adipose tissue and the heart of salt-sensitive hypertensive rats. Several miRNAs influence AGT expression and are associated with cardiovascular diseases. Expression of both ACE and ACE2 genes is regulated by DNA methylation, histone modifications, and miRNAs. Expression of both angiotensinogen and CYP11B2 is reversibly regulated by epigenetic modifications and is related to salt-sensitive hypertension. The mineralocorticoid receptor (MR) exists in cardiovascular and renal tissues, in which many miRNAs influence expression and contribute to the pathogenesis of hypertension. Expression of the 11beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) gene is also regulated by methylation and miRNAs. Epigenetic regulation of renal and vascular HSD11B2 is an important pathogenetic mechanism for salt-sensitive hypertension.


Assuntos
Metilação de DNA , Epigênese Genética , Hipertensão , Sistema Renina-Angiotensina , Sistema Renina-Angiotensina/genética , Hipertensão/genética , Hipertensão/metabolismo , Animais , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo
8.
Crit Care Explor ; 6(8): e1134, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39110074

RESUMO

IMPORTANCE: Pediatric acute kidney injury (AKI) is a prevalent and morbid complication of shock. Its pathogenesis and early identification remain elusive. OBJECTIVES: We aim to determine whether renal blood flow (RBF) measurements by point-of-care ultrasound (POCUS) and renin-angiotensin-aldosterone system (RAAS) hormones in pediatric shock associate with vasoactive requirements and AKI. DESIGN, SETTING, AND PARTICIPANTS: This is a single-center prospective, noninterventional observational cohort study in one tertiary PICU in North American from 2020 to 2022 that enrolled children younger than 18 years with shock without preexisting end-stage renal disease. MAIN OUTCOMES AND MEASURES: RBF was measured by POCUS on hospital days 1 and 3 and plasma RAAS hormone levels were measured on day 1. The primary outcome was the presence of AKI by Kidney Disease Improving Global Outcomes criteria at first ultrasound with key secondary outcomes of creatinine, blood urea nitrogen (BUN), Vasoactive-Inotrope Score (VIS), and norepinephrine equivalent dosing (NED) 48 hours after first ultrasound. RESULTS: Fifty patients were recruited (20 with AKI, mean age 10.5 yr, 48% female). POCUS RBF showed lower qualitative blood flow (power Doppler ultrasound [PDU] score) and higher regional vascular resistance (renal resistive index [RRI]) in children with AKI (p = 0.017 and p = 0.0007). Renin and aldosterone levels were higher in the AKI cohort (p = 0.003 and p = 0.007). Admission RRI and PDU associated with higher day 3 VIS and NED after adjusting for age, day 1 VIS, and RAAS hormones. Admission renin associated with higher day 3 creatinine and BUN after adjusting for age, day 1 VIS, and the ultrasound parameters. CONCLUSIONS AND RELEVANCE: In pediatric shock, kidney blood flow was abnormal and renin and aldosterone were elevated in those with AKI. Kidney blood flow abnormalities are independently associated with future cardiovascular dysfunction; renin elevations are independently associated with future kidney dysfunction. Kidney blood flow by POCUS may identify children who will have persistent as opposed to resolving AKI. RAAS perturbations may drive AKI in pediatric shock.


Assuntos
Injúria Renal Aguda , Circulação Renal , Sistema Renina-Angiotensina , Humanos , Feminino , Criança , Masculino , Estudos Prospectivos , Injúria Renal Aguda/sangue , Injúria Renal Aguda/fisiopatologia , Injúria Renal Aguda/etiologia , Sistema Renina-Angiotensina/fisiologia , Adolescente , Choque/sangue , Choque/fisiopatologia , Pré-Escolar , Estudos de Coortes , Lactente , Rim/fisiopatologia , Rim/irrigação sanguínea , Rim/diagnóstico por imagem
9.
CMAJ ; 196(27): E931-E939, 2024 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-39134317

RESUMO

BACKGROUND: Hepatitis B virus (HBV) infection is a common cause of liver-related morbidity and mortality. Evidence suggests that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) decrease liver fibrosis, an intermediate step between liver injury and hepatocellular carcinoma (HCC). Our aim was to investigate the association between the use of ACEIs and ARBs on incident HCC and liver-related mortality among patients with HBV infection. METHODS: We conducted a population-based study on a new-user cohort of patients seen at 24 hospitals across China. We included adult patients with HBV infection who started ACEIs or ARBs (ACEIs/ARBs), or calcium channel blockers or thiazide diuretics (CCBs/THZs) from January 2012 to December 2022. The primary outcome was incident HCC; secondary outcomes were liver-related mortality and new-onset cirrhosis. We used propensity score matching and Cox proportional hazards regression to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of study outcomes. RESULTS: Among 32 692 eligible patients (median age 58 [interquartile range (IQR) 48-68] yr, and 18 804 male [57.5%]), we matched 9946 pairs of patients starting ACEIs/ARBs or CCBs/THZs. During a mean follow-up of 2.3 years, the incidence rate of HCC per 1000 person-years was 4.11 and 5.94 among patients who started ACEIs/ARBs and CCBs/THZs, respectively, in the matched cohort. Use of ACEIs/ARBs was associated with lower risks of incident HCC (HR 0.66, 95% CI 0.50-0.86), liver-related mortality (HR 0.77, 95% CI 0.64-0.93), and new-onset cirrhosis (HR 0.81, 95% CI 0.70-0.94). INTERPRETATION: In this cohort of patients with HBV infection, new users of ACEIs/ARBs had a lower risk of incident HCC, liver-related mortality, and new-onset cirrhosis than new users of CCBs/THZs.


Assuntos
Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/epidemiologia , Masculino , Neoplasias Hepáticas/epidemiologia , Feminino , Pessoa de Meia-Idade , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Antagonistas de Receptores de Angiotensina/efeitos adversos , China/epidemiologia , Hepatite B/complicações , Cirrose Hepática , Incidência , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Pontuação de Propensão , Modelos de Riscos Proporcionais , Fatores de Risco , Sistema Renina-Angiotensina/efeitos dos fármacos
10.
Front Endocrinol (Lausanne) ; 15: 1424207, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39140032

RESUMO

Background: Prior research has highlighted the association between uric acid (UA) and the activation of the renin-angiotensin-aldosterone system (RAAS). However, the specific relationship between aldosterone, the RAAS's end product, and UA-related diseases remains poorly understood. This study aims to clarify the impact of aldosterone on the development and progression of hyperuricemia and gout in hypertensive patients. Methods: Our study involved 34534 hypertensive participants, assessing plasma aldosterone concentration (PAC)'s role in UA-related diseases, mainly hyperuricemia and gout. We applied multiple logistic regression to investigate the impact of PAC and used restricted cubic splines (RCS) for examining the dose-response relationship between PAC and these diseases. To gain deeper insights, we conducted threshold analyses, further clarifying the nature of this relationship. Finally, we undertook subgroup analyses to evaluate PAC's effects across diverse conditions and among different subgroups. Results: Multivariate logistic regression analysis revealed a significant correlation between the occurrence of hyperuricemia and gout and the elevation of PAC levels. Compared to the first quartile (Q1) group, groups Q2, Q3, and Q4 all exhibited a significantly increased risk of occurrence. Moreover, the conducted RCS analysis demonstrated a significant nonlinear dose-response relationship, especially when PAC was greater than 14 ng/dL, with a further increased risk of hyperuricemia and gout. Finally, comprehensive subgroup analyses consistently reinforced these findings. Conclusion: This study demonstrates a close association between elevated PAC levels and the development of UA-related diseases, namely hyperuricemia and gout, in hypertensive patients. Further prospective studies are warranted to confirm and validate this relationship.


Assuntos
Aldosterona , Gota , Hipertensão , Hiperuricemia , Humanos , Hiperuricemia/sangue , Hiperuricemia/complicações , Gota/sangue , Gota/epidemiologia , Gota/complicações , Masculino , Aldosterona/sangue , Hipertensão/sangue , Hipertensão/complicações , Pessoa de Meia-Idade , Feminino , Idoso , Ácido Úrico/sangue , Sistema Renina-Angiotensina/fisiologia , Adulto
11.
Rev Med Virol ; 34(5): e2577, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39215460

RESUMO

Dengue is a disease caused by a flavivirus (DENV) and transmitted by the bite of a mosquito, primarily the Aedes aegypti and Aedes albopictus species. Previous studies have demonstrated a relationship between the host gut microbiota and the evolution of dengue. It seems to be a bidirectional relationship, in which the DENV can affect the microbiota by inducing alterations related to intestinal permeability, leading to the release of molecules from microbiota dysbiosis that can influence the evolution of dengue. The role of angiotensin II (Ang II) in the microbiota/dengue relationship is not well understood, but it is known that the renin-angiotensin system (RAS) is present in the intestinal tract and interacts with the gut microbiota. The possible effect of Ang II on the microbiota/Ang II/dengue relationship can be summarised as follows: the presence of Ang II induced hypertension, the increase in angiotensinogen, chymase, and microRNAs during the disease, the induction of vascular dysfunction, the production of trimethylamine N-oxide and the brain/microbiota relationship, all of which are elements present in dengue that could be part of the microbiota/Ang II/dengue interactions. These findings suggest the potential use of Ang II synthesis blockers and the use of AT1 receptor antagonists as therapeutic drugs in dengue.


Assuntos
Dengue , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Dengue/virologia , Animais , Disbiose/microbiologia , Angiotensina II/metabolismo , Vírus da Dengue/fisiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Aedes/microbiologia , Aedes/virologia
12.
Int J Mol Sci ; 25(16)2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39201774

RESUMO

Mineralocorticoid receptor antagonists (MRAs) are one of the renin-angiotensin-aldosterone system inhibitors widely used in clinical practice. While spironolactone and eplerenone have a long-standing profile in clinical medicine, finerenone is a novel agent within the MRA class. It has a higher specificity for mineralocorticoid receptors, eliciting less pronounced adverse effects. Although approved for clinical use in patients with chronic kidney disease and heart failure, intensive non-clinical research aims to further elucidate its mechanism of action, including dose-related selectivity. Within the field, animal models remain the gold standard for non-clinical testing of drug pharmacological and toxicological properties. Their role, however, has been challenged by recent advances in in vitro models, mainly through sophisticated analytical tools and developments in data analysis. Currently, in vitro models are gaining momentum as possible platforms for advanced pharmacological and pathophysiological studies. This article focuses on past, current, and possibly future in vitro cell models research with clinically relevant MRAs.


Assuntos
Antagonistas de Receptores de Mineralocorticoides , Receptores de Mineralocorticoides , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Humanos , Animais , Receptores de Mineralocorticoides/metabolismo , Espironolactona/farmacologia , Espironolactona/análogos & derivados , Espironolactona/uso terapêutico , Eplerenona/farmacologia , Eplerenona/uso terapêutico , Naftiridinas/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Sistema Renina-Angiotensina/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo
13.
Nutrients ; 16(16)2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39203744

RESUMO

Lactoferrin, a glycoprotein derived from breastmilk, is recognized for its health benefits in infants and children; however, its protective effects when administered during gestation and lactation against offspring hypertension remain unclear. This study aimed to investigate whether maternal lactoferrin supplementation could prevent hypertension in offspring born to mothers with chronic kidney disease (CKD), with a focus on nitric oxide (NO), renin-angiotensin system (RAS) regulation, and alterations in gut microbiota and short-chain fatty acids (SCFAs). Prior to pregnancy, female rats were subjected to a 0.5% adenine diet for 3 weeks to induce CKD. During pregnancy and lactation, pregnant rats received one of four diets: normal chow, 0.5% adenine diet, 10% lactoferrin diet, or adenine diet supplemented with lactoferrin. Male offspring were euthanized at 12 weeks of age (n = 8 per group). Supplementation with lactoferrin during gestation and lactation prevented hypertension in adult offspring induced by a maternal adenine diet. The maternal adenine diet caused a decrease in the index of NO availability, which was restored by 67% with maternal LF supplementation. Additionally, LF was related to the regulation of the RAS, as evidenced by a reduced renal expression of renin and the angiotensin II type 1 receptor. Combined maternal adenine and LF diets altered beta diversity, shifted the offspring's gut microbiota, decreased propionate levels, and reduced the renal expression of SCFA receptors. The beneficial effects of lactoferrin are likely mediated through enhanced NO availability, rebalancing the RAS, and alterations in gut microbiota composition and SCFAs. Our findings suggest that maternal lactoferrin supplementation improves hypertension in offspring in a model of adenine-induced CKD, bringing us closer to potentially translating lactoferrin supplementation clinically for children born to mothers with CKD.


Assuntos
Adenina , Suplementos Nutricionais , Microbioma Gastrointestinal , Hipertensão , Lactação , Lactoferrina , Fenômenos Fisiológicos da Nutrição Materna , Sistema Renina-Angiotensina , Animais , Lactoferrina/administração & dosagem , Lactoferrina/farmacologia , Feminino , Gravidez , Masculino , Hipertensão/prevenção & controle , Hipertensão/induzido quimicamente , Hipertensão/etiologia , Ratos , Sistema Renina-Angiotensina/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Óxido Nítrico/metabolismo , Insuficiência Renal Crônica/prevenção & controle , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/induzido quimicamente , Ácidos Graxos Voláteis/metabolismo , Ratos Sprague-Dawley , Dieta
14.
Int J Mol Sci ; 25(16)2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39201324

RESUMO

Premenopausal women generally exhibit lower blood pressure and a lower prevalence of hypertension than men of the same age, but these differences reverse postmenopause due to estrogen withdrawal. Sexual dimorphism has been described in different components of kidney physiology and pathophysiology, including the renin-angiotensin-aldosterone system, endothelin system, and tubular transporters. This review explores the sex-specific differences in kidney function and blood pressure regulation. Understanding these differences provides insights into potential therapeutic targets for managing hypertension and kidney diseases, considering the patient's sex and hormonal status.


Assuntos
Pressão Sanguínea , Hipertensão , Rim , Sistema Renina-Angiotensina , Caracteres Sexuais , Humanos , Pressão Sanguínea/fisiologia , Rim/metabolismo , Sistema Renina-Angiotensina/fisiologia , Feminino , Hipertensão/fisiopatologia , Hipertensão/metabolismo , Masculino , Animais , Fatores Sexuais
15.
Cell Signal ; 122: 111335, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39117253

RESUMO

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.


Assuntos
Sistema Renina-Angiotensina , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
16.
Cell Signal ; 122: 111343, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39127136

RESUMO

Glaucoma, a leading cause of blindness worldwide, encompasses a group of pathological conditions affecting the optic nerve and is characterized by progressive retinal ganglion cell loss, cupping of the optic nerve head, and distinct visual field defects. While elevated intraocular pressure (IOP) is the main risk factor for glaucoma, many patients do not have elevated IOP. Consequently, other risk factors, such as ocular blood flow abnormalities and immunological factors, have been implicated in its pathophysiology. Traditional therapeutic strategies primarily aim to reduce IOP, but there is growing interest in developing novel treatment approaches to improve disease management and reduce the high rates of severe visual impairment. In this context, targeting the ocular renin-angiotensin-aldosterone system (RAAS) has been found as a potential curative strategy. The RAAS contributes to glaucoma development through key effectors such as prorenin, angiotensin II, and aldosterone. Recent evidence has highlighted the potential of using RAAS modulators to combat glaucoma, yielding encouraging results. Our study aims to explore the molecular pathways linking the ocular RAAS and glaucoma, summarizing recent advances that elucidate the role of the RAAS in triggering oxidative stress, inflammation, and remodelling in the pathogenesis of glaucoma. Additionally, we will present emerging therapeutic approaches that utilize RAAS modulators and antioxidants to slow the progression of glaucoma.


Assuntos
Glaucoma , Sistema Renina-Angiotensina , Animais , Humanos , Glaucoma/metabolismo , Glaucoma/terapia , Pressão Intraocular , Estresse Oxidativo , Transdução de Sinais , Aldosterona/metabolismo
17.
Vascul Pharmacol ; 156: 107414, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39089528

RESUMO

Sepsis and atherosclerotic cardiovascular disease (ASCVD) are major health challenges involving complex processes like inflammation, renin-angiotensin system (RAS) dysregulation, and thrombosis. Despite distinct clinical symptoms, both conditions share mechanisms mediated by bradykinin. This review explores bradykinin's role in inflammation, RAS modulation, and thrombosis in sepsis and ASCVD. In sepsis, variable kininogen-bradykinin levels may correlate with disease severity and progression, though the effect of bradykinin receptor modulation on inflammation remains uncertain. RAS activation is present in both diseases, with sepsis showing variable or low levels of Ang II, ACE, and ACE2, while ASCVD consistently exhibits elevated levels. Bradykinin may act as a mediator for ACE2 and AT2 receptor effects in RAS regulation. It may influence clotting and fibrinolysis in sepsis-associated coagulopathy, but evidence for an antithrombotic effect in ASCVD is insufficient. Understanding bradykinin's role in these shared pathologies could guide therapeutic and monitoring strategies and inform future research.


Assuntos
Aterosclerose , Coagulação Sanguínea , Bradicinina , Sistema Renina-Angiotensina , Sepse , Transdução de Sinais , Humanos , Bradicinina/metabolismo , Sepse/fisiopatologia , Sepse/metabolismo , Sepse/sangue , Aterosclerose/fisiopatologia , Aterosclerose/metabolismo , Aterosclerose/sangue , Animais , Coagulação Sanguínea/efeitos dos fármacos , Receptores da Bradicinina/metabolismo , Trombose/fisiopatologia , Trombose/sangue , Trombose/metabolismo
18.
Am J Reprod Immunol ; 92(2): e13915, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39132825

RESUMO

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.


Assuntos
COVID-19 , Pré-Eclâmpsia , Complicações Infecciosas na Gravidez , SARS-CoV-2 , Humanos , COVID-19/fisiopatologia , COVID-19/imunologia , Gravidez , Feminino , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/imunologia , SARS-CoV-2/fisiologia , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Sistema Renina-Angiotensina
19.
BMC Nephrol ; 25(1): 268, 2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39179976

RESUMO

BACKGROUND: Urinary Dickkopf 3 (DKK3) excretion is a recently established biomarker of renal functional development. Its excretion into the peritoneal cavity has not been reported. We here studied DKK3 in peritoneal dialysis. METHODS: DKK3 was assessed in serum, urine and dialysate in a prevalent adult peritoneal dialysis cohort and its concentration analyzed in relation to creatinine and clinical characteristics. RESULTS: Highest DKK3 concentrations were found in serum, followed by urine. Dialysate concentrations were significantly lower. Dialysate DKK3 correlated with both other compartments. Serum, dialysate and urine values were stable during three months of follow-up. Continuous ambulatory dialysis (CAPD) but not cycler-assisted peritoneal dialysis (CCPD) volume-dependently increased peritoneal DKK3 in relation to creatinine. RAAS blockade significantly decreased urinary, but not serum or peritoneal DKK3. CONCLUSION: Our data provide a detailed characterization of DKK3 in peritoneal dialysis. They support the notion that the RAAS system is essential for renal DKK3 handling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Diálise Peritoneal , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Quimiocinas/sangue , Quimiocinas/metabolismo , Idoso , Adulto , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Falência Renal Crônica/terapia , Falência Renal Crônica/metabolismo , Biomarcadores/sangue , Soluções para Diálise/metabolismo , Rim/metabolismo , Peritônio/metabolismo , Diálise Peritoneal Ambulatorial Contínua , Sistema Renina-Angiotensina/fisiologia , Creatinina/urina , Creatinina/sangue , Creatinina/metabolismo
20.
Int J Mol Sci ; 25(15)2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39125938

RESUMO

Insulin signaling is vital for regulating cellular metabolism, growth, and survival pathways, particularly in tissues such as adipose, skeletal muscle, liver, and brain. Its role in the heart, however, is less well-explored. The heart, requiring significant ATP to fuel its contractile machinery, relies on insulin signaling to manage myocardial substrate supply and directly affect cardiac muscle metabolism. This review investigates the insulin-heart axis, focusing on insulin's multifaceted influence on cardiac function, from metabolic regulation to the development of physiological cardiac hypertrophy. A central theme of this review is the pathophysiology of insulin resistance and its profound implications for cardiac health. We discuss the intricate molecular mechanisms by which insulin signaling modulates glucose and fatty acid metabolism in cardiomyocytes, emphasizing its pivotal role in maintaining cardiac energy homeostasis. Insulin resistance disrupts these processes, leading to significant cardiac metabolic disturbances, autonomic dysfunction, subcellular signaling abnormalities, and activation of the renin-angiotensin-aldosterone system. These factors collectively contribute to the progression of diabetic cardiomyopathy and other cardiovascular diseases. Insulin resistance is linked to hypertrophy, fibrosis, diastolic dysfunction, and systolic heart failure, exacerbating the risk of coronary artery disease and heart failure. Understanding the insulin-heart axis is crucial for developing therapeutic strategies to mitigate the cardiovascular complications associated with insulin resistance and diabetes.


Assuntos
Resistência à Insulina , Insulina , Transdução de Sinais , Humanos , Animais , Insulina/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Coração/fisiologia , Coração/fisiopatologia , Sistema Renina-Angiotensina/fisiologia
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