RESUMO
This review highlights the molecular basis of salt sensitivity in hypertension, with a focus on the regulation of sodium transport in the distal nephron. Sodium reabsorption in this region is often linked to the actions of aldosterone, although in recent years numerous findings have been reported on the aldosterone-independent pathway of acquiring salt sensitivity by potassium deficiency or potassium loading. The key to this discussion is the interplay, through extracellular potassium concentration, between the first part of the tubules expressing the Na+-Cl- cotransporter (NCC) and the second part expressing the epithelial sodium channel (ENaC). The molecular pathways such as WNK-SPAK/OSR1 signaling, KLHL3-CUL3 complex, protein phosphatases and mTORC2-Nedd4L pathway are described as the mechanism by which salt sensitivity on blood pressure is acquired in response to changes in physiological conditions including potassium depletion or loading. This review highlights the potential for targeting these molecular pathways to develop novel therapeutic strategies for the treatment of salt-sensitive hypertension, the mechanism of which remains to be elucidated.
RESUMO
It has been more than 60 years since the colonized genetic model of hypertension was first established. Model animals contribute greatly to the advance of understanding of the pathophysiology and development of effective therapy. In this review, the author focuses on two points: gene-related biomarkers and the use of humanized mice to search for biomarkers. First, the author provides an overview of the history of the establishment of hypertension and salt-sensitivity model rats, as well as advances in genetic analysis of causative genes of hypertension and the theory of renal causes of salt-sensitive hypertension. The recent animal model analysis adds the notion of the importance of epigenetic alterations in addition to the genetic causes of hypertension. Both germline mutations and epigenetic analysis of congenic animal models are complementary and should carry out furtherly. Among epigenetic factors, non-coding RNA is a promising new 'liquid biopsy' which is originally applied to diagnose cancers by detecting cancer cell-derived DNA, RNA, or other molecules in a person's body fluid and now it can be applied to any pathophysiological conditions. Then, the author reviews the usefulness of humanized mice. Few studies have used such mice in cardiovascular research, but the present study highlights a study of immune-related disease and the search for biomarkers in such mice. Perspectives on using humanized mice in cardiovascular research are discussed.
Assuntos
Doenças Cardiovasculares , Hipertensão , Ratos , Camundongos , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/complicações , Modelos Animais , Rim , Marcadores Genéticos , Modelos Animais de DoençasRESUMO
Renal fibrosis is an inevitable process in the progression of chronic kidney disease (CKD). Angiogenesis plays an important role in this process. Vascular endothelial cells are involved in renal fibrosis by phenotypic transformation and secretion of extracellular matrix. Aldosterone stimulates mineralocorticoid receptor (MR) activation and induces inflammation, which is important for angiogenesis. Clinically, MR blockers (MRBs) have a protective effect on damaged kidneys, which may be associated with inhibition of angiogenesis. In this study, we used aldosterone-infused mice and found that aldosterone induced angiogenesis and that endothelial-mesenchymal transition (EndMT) in neovascular endothelial cells was involved in renal fibrosis. Notably, aldosterone induced inflammation and stimulated macrophages to secrete vascular endothelial growth factor (VEGF) A to regulate angiogenesis by activating MR, whereas EndMT occurred in response to transforming growth factor-ß1 (TGF-ß1) induction and participated in renal fibrosis. These effects were antagonized by the MRB esaxerenone. These findings suggest that reducing angiogenesis may be an effective strategy for treating renal fibrosis.
Assuntos
Nefropatias , Fator de Crescimento Transformador beta1 , Camundongos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Aldosterona/farmacologia , Aldosterona/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Células Endoteliais/metabolismo , Transdução de Sinais , Rim/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Fibrose , Inflamação/metabolismo , Transição Epitelial-MesenquimalRESUMO
Atopic dermatitis (AD) is the most common inflammatory skin disease in children. The serum level of thymus and activation-regulated chemokine (TARC) is a useful AD index to reflect disease severity; however, it requires blood collection from young children. In comparison, urine samples are easier to collect in a pediatric clinical setting. Here, we analyzed the lipids excreted in urine to identify a diagnostic biomarker for AD. We generated a murine dermatitis model by repeated topical application of 2,4-dinitrofluorobenzene (DNFB) or tape-stripping the dorsal skin. Lipid metabolites excreted in the urine were comprehensively analyzed using liquid chromatography-tandem mass spectrometry. To corroborate our findings, we also analyzed urine samples from patients with AD. DNFB application induced AD-like skin lesions, including epidermal thickening, infiltration of eosinophils and T cells, and an increase in Th2 cytokine levels. Assessment of lipids excreted in urine showed a dominance of prostaglandins (PGs), namely, a PGF2α metabolite (13,14-dihydro-15-keto-tetranor-PGF1α ), a PGE2 metabolite (13,14-dihydro-15-keto-tetranor-PGE2 ), and a PGD2 metabolite (13,14-dihydro-15-keto PGJ2 ). mRNA and protein expression of PGF2α , PGE2 , and PGD2 synthase was upregulated in DNFB-treated skin. The tape-stripping model also caused dermatitis but without Th2 inflammation; urine PGF2α and PGD2 metabolite levels remained unaffected. Finally, we confirmed that the urinary levels of the aforementioned PG metabolites, as well as PGI2 metabolite, 6,15-diketo-13,14-dihydro-PGF1α and arachidonic acid metabolite, 17-hydroxyeicosatetraenoic acid (17-HETE) increased in patients with AD. Our data highlights the unique urinary lipid profile in patients with AD, which may provide insight into novel urinary biomarkers for AD diagnosis.
Assuntos
Dermatite Atópica/diagnóstico , Dermatite Atópica/urina , Prostaglandinas/urina , Índice de Gravidade de Doença , Administração Cutânea , Animais , Biomarcadores/urina , Criança , Pré-Escolar , Cromatografia Líquida/métodos , Dermatite Atópica/induzido quimicamente , Dinitrofluorbenzeno/administração & dosagem , Dinitrofluorbenzeno/efeitos adversos , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pele/efeitos dos fármacos , Pele/metabolismo , Espectrometria de Massas em Tandem/métodosRESUMO
Chronic kidney disease (CKD) is a common clinical disease with an increasing incidence, affecting 10 to 15% of the world's population. Hypertension is the most common and modifiable risk factor for preventing adverse cardiovascular outcomes in patients with CKD. A survey from developed countries shows that 47% of hypertensive patients over the age of 20 have uncontrolled blood pressure (BP), and the control rate is even lower in developing countries. CKD is both a common cause of uncontrolled hypertension and a risk factor for altered sequelae. In particular, studies have demonstrated that abnormal blood-pressure patterns in CKD patients, such as non-dipping-blood-pressure patterns, are associated with a significantly increased risk of cardiovascular (CV) disease. The distal convoluted tubule (DCT) is a region of the kidney, and although only 5-10% of the sodium (Na+) filtered by the glomerulus is reabsorbed by DCT, most studies agree that Na-Cl cotransporter (NCC) in human, rabbit, mouse, and rat kidneys is the most important route of sodium reabsorption across the DCT for maintaining the homeostasis of sodium. The regulation of NCC involves a large and complex network structure, including certain physiological factors, kinases, scaffold proteins, transporter phosphorylation, and other aspects. This regulation network includes various levels. Naturally, cross-talk between the components of this system must occur in order to relay the important signals to the transporter to play its role. Knowledge of the mechanisms regulating NCC activation is critical for understanding and treating hypertension and CKD. Previous studies from our laboratory have investigated the mechanisms through which NCC is activated in several different models. In the following sections, we review the literature on the mechanisms of NCC in relation to hypertension in CKD.
Assuntos
Hipertensão , Insuficiência Renal Crônica , Ratos , Humanos , Camundongos , Animais , Coelhos , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Hipertensão/metabolismo , Rim/metabolismo , Sódio/metabolismo , Túbulos Renais Distais/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismoRESUMO
BACKGROUND: Regulation of sodium chloride transport in the aldosterone-sensitive distal nephron is essential for fluid homeostasis and BP control. The chloride-bicarbonate exchanger pendrin in ß-intercalated cells, along with sodium chloride cotransporter (NCC) in distal convoluted tubules, complementarily regulate sodium chloride handling, which is controlled by the renin-angiotensin-aldosterone system. METHODS: Using mice with mineralocorticoid receptor deletion in intercalated cells, we examined the mechanism and roles of pendrin upregulation via mineralocorticoid receptor in two different models of renin-angiotensin-aldosterone system activation. We also used aldosterone-treated NCC knockout mice to examine the role of pendrin regulation in salt-sensitive hypertension. RESULTS: Deletion of mineralocorticoid receptor in intercalated cells suppressed the increase in renal pendrin expression induced by either exogenous angiotensin II infusion or endogenous angiotensin II upregulation via salt restriction. When fed a low-salt diet, intercalated cell-specific mineralocorticoid receptor knockout mice with suppression of pendrin upregulation showed BP reduction that was attenuated by compensatory activation of NCC. In contrast, upregulation of pendrin induced by aldosterone excess combined with a high-salt diet was scarcely affected by deletion of mineralocorticoid receptor in intercalated cells, but depended instead on hypokalemic alkalosis through the activated mineralocorticoid receptor-epithelial sodium channel cascade in principal cells. In aldosterone-treated NCC knockout mice showing upregulation of pendrin, potassium supplementation corrected alkalosis and inhibited the pendrin upregulation, thereby lowering BP. CONCLUSIONS: In conjunction with NCC, the two pathways of pendrin upregulation, induced by angiotensin II through mineralocorticoid receptor activation in intercalated cells and by alkalosis through mineralocorticoid receptor activation in principal cells, play important roles in fluid homeostasis during salt depletion and salt-sensitive hypertension mediated by aldosterone excess.
Assuntos
Hipertensão/etiologia , Néfrons/metabolismo , Néfrons/patologia , Receptores de Mineralocorticoides/fisiologia , Simportadores de Cloreto de Sódio/fisiologia , Transportadores de Sulfato/metabolismo , Aldosterona , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Sistema Renina-Angiotensina/fisiologiaRESUMO
To investigate the cause of salt sensitivity in a normotensive animal model, we treated rats with a low-dose of the nitric oxide synthase inhibitor, L-NAME, that does not elevate blood pressure per se or induce kidney fibrosis. A high salt diet increased the circulating blood volume both in L-NAME-treated and nontreated animals for the first 24 hours. Thereafter, the blood volume increase persisted only in the L-NAME-treated rats. Blood pressure was higher in the L-NAME-treated group from the start of high salt diet exposure. Within the first 24 hours of salt loading, the L-NAME treated animals failed to show vasodilation and maintained high systemic vascular resistance in response to blood volume expansion. After four weeks on the high salt diet, the slope of the pressure-natriuresis curve was blunted in the L-NAME-treated group. An increase in natriuresis was observed after treatment with hydrochlorothiazide, but not amiloride, a change observed in parallel with increased phosphorylated sodium-chloride cotransporter (NCC). In contrast, a change in blood pressure was not observed in L-NAME-treated NCC-deficient mice fed a high salt diet. Moreover, direct L-NAME-induced NCC activation was demonstrated in cells of the mouse distal convoluted tubule. The vasodilatator, sodium nitroprusside, downregulated phosphorylated NCC expression. The effect of L-NAME on phosphorylated NCC was blocked by both the SPAK inhibitor STOCK2S-26016 and the superoxide dismutase mimetic TEMPO which also attenuated salt-induced hypertension. These results suggest that the initiation of salt sensitivity in normotensive rodents could be due to hyporeactivity of the vasculature and that maintaining blood pressure could result in a high circulating volume due to inappropriate NCC activity in the low-dose L-NAME model. Thus, even slightly impaired nitric oxide production may be important in salt sensitivity regulation in healthy rodents.
Assuntos
Hipertensão , Simportadores de Cloreto de Sódio , Animais , Pressão Sanguínea , Volume Sanguíneo , Hipertensão/induzido quimicamente , Camundongos , NG-Nitroarginina Metil Éster , Ratos , RoedoresRESUMO
The renin-angiotensin-aldosterone system has an important role in the control of fluid homeostasis and BP during volume depletion. Dietary salt restriction elevates circulating angiotensin II (AngII) and aldosterone levels, increasing levels of the Cl-/HCO3- exchanger pendrin in ß-intercalated cells and the Na+-Cl- cotransporter (NCC) in distal convoluted tubules. However, the independent roles of AngII and aldosterone in regulating these levels remain unclear. In C57BL/6J mice receiving a low-salt diet or AngII infusion, we evaluated the membrane protein abundance of pendrin and NCC; assessed the phosphorylation of the mineralocorticoid receptor, which selectively inhibits aldosterone binding in intercalated cells; and measured BP by radiotelemetry in pendrin-knockout and wild-type mice. A low-salt diet or AngII infusion upregulated NCC and pendrin levels, decreased the phosphorylation of mineralocorticoid receptor in ß-intercalated cells, and increased plasma aldosterone levels. Notably, a low-salt diet did not alter BP in wild-type mice, but significantly decreased BP in pendrin-knockout mice. To dissect the roles of AngII and aldosterone, we performed adrenalectomies in mice to remove aldosterone from the circulation. In adrenalectomized mice, AngII infusion again upregulated NCC expression, but did not affect pendrin expression despite the decreased phosphorylation of mineralocorticoid receptor. By contrast, AngII and aldosterone coadministration markedly elevated pendrin levels in adrenalectomized mice. Our results indicate that aldosterone is necessary for AngII-induced pendrin upregulation, and suggest that pendrin contributes to the maintenance of normal BP in cooperation with NCC during activation of the renin-angiotensin-aldosterone system by dietary salt restriction.
Assuntos
Aldosterona/sangue , Angiotensina II/farmacologia , Simportadores de Cloreto de Sódio/metabolismo , Transportadores de Sulfato/metabolismo , Vasoconstritores/farmacologia , Adrenalectomia , Aldosterona/farmacologia , Animais , Pressão Sanguínea/genética , Túbulos Renais Distais/citologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Receptores de Mineralocorticoides/metabolismo , Cloreto de Sódio na Dieta/administração & dosagem , Transportadores de Sulfato/genética , Regulação para Cima/efeitos dos fármacosAssuntos
Hipersensibilidade , Prostaglandina D2 , Alérgenos , Humanos , Prostaglandina D2/metabolismoRESUMO
Pulmonary arterial hypertension (PAH) is prevalent in patients with obstructive sleep apnea syndrome (OSAS). Aging induces arginase activation and reduces nitric oxide (NO) production in the arteries. Intermittent hypoxia (IH), conferred by cycles of brief hypoxia and normoxia, contributes to OSAS pathogenesis. Here, we studied the role of arginase and aging in the pathogenesis of PAH in adult (9-mo-old) and young (2-mo-old) male Sprague-Dawley rats subjected to IH or normoxia for 4 weeks and analyzed them with a pressure-volume catheter inserted into the right ventricle (RV) and by pulsed Doppler echocardiography. Western blot analysis was conducted on arginase, NO synthase isoforms, and nitrotyrosine. IH induced PAH, as shown by increased RV systolic pressure and RV hypertrophy, in adult rats but not in young rats. IH increased expression levels of arginase I and II proteins in the adult rats. IH also increased arginase I expression in the pulmonary artery endothelium and arginase II in the pulmonary artery adventitia. Furthermore, IH reduced pulmonary levels of nitrate and nitrite but increased nitrotyrosine levels in adult rats. An arginase inhibitor (N(ω)-hydroxy-nor-1-arginine) prevented IH-induced PAH and normalized nitrite and nitrate levels in adult rats. IH induced arginase up-regulation and PAH in adult rats, but not in young rats, through reduced NO production. Our findings suggest that arginase inhibition prevents or reverses PAH.
Assuntos
Arginase/metabolismo , Hipertensão/enzimologia , Envelhecimento , Animais , Hipóxia Celular , Ativação Enzimática , Pulmão/enzimologia , Masculino , Nitratos/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Nitritos/metabolismo , Artéria Pulmonar/enzimologia , Artéria Pulmonar/fisiopatologia , Ratos Sprague-Dawley , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMO
BACKGROUND: It is widely known that salt is an accelerating factor for the progression of metabolic syndrome and causes cardiovascular diseases, most likely due to its pro-oxidant properties. We hypothesized that excessive salt intake also facilitates the development of nonalcoholic steatohepatitis (NASH), which is frequently associated with metabolic syndrome. METHODS: We examined the exacerbating effect of high-salt diet on high-fat diet-induced liver injury in a susceptible model to oxidative stress, apoE knockout and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) transgenic mice. RESULTS: High-salt diet led to NASH in high-fat diet-fed LOX-1 transgenic/apoE knockout mice without affecting high-fat diet-induced dyslipidemia or hepatic triglyceride accumulation. Additionally, a high-salt and high-fat diet stimulated oxidative stress production and inflammatory reaction to a greater extent than did a high-fat diet in the liver of LOX-1 transgenic/apoE knockout mice. CONCLUSIONS: We demonstrated that high-salt diet exacerbated NASH in high-fat diet-fed LOX-1 transgenic /apoE knockout mice and that this effect was associated with the stimulation of oxidative and inflammatory processes; this is the first study to suggest the important role of excessive salt intake in the development of NASH.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Dislipidemias/complicações , Fígado Gorduroso/etiologia , Estresse Oxidativo/efeitos dos fármacos , Sódio na Dieta/efeitos adversos , Animais , Western Blotting , Dislipidemias/patologia , Fígado Gorduroso/patologia , Fibrose/etiologia , Inflamação/etiologia , Fígado/química , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , NADP/metabolismo , Estresse Oxidativo/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptores Depuradores Classe E/biossíntese , Receptores Depuradores Classe E/genética , Superóxidos/análiseRESUMO
Biomarkers for hypertension should be widely applied to diagnosis, evaluation for risks and therapeutic efficiency. The guidelines from Japan and ESH/ESC list markers to evaluate cardiovascular risks and organ damages which should be applied after careful physical examination and sensitivity, specificity and likelihood of markers must be taken into account. Proteome, metabolome analysis, microRNAs or new markers in blood and urine is promising for future diagnosis of salt-sensitivity, tubular damages and other organ damages. Accumulation of evidence for established markers such as CAVI, AI, FMD or other markers are expected.
Assuntos
Hipertensão/sangue , Anti-Hipertensivos/uso terapêutico , Biomarcadores/sangue , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Metaboloma , MicroRNAs/genética , Proteoma/análiseRESUMO
Fibroblast growth factor 23 (FGF23) is a phosphate-regulating hormone that acts primarily on the kidney and parathyroid. With declining kidney function there is an increase in circulating FGF23 levels, which is associated with vascular calcification and mortality in chronic kidney disease. Whether FGF23 exerts direct effects on vasculature is unclear. We evaluated the expression of Klotho and FGF receptors in rat aortic rings and rat aorta vascular smooth muscle cells maintained in culture by reverse transcription-PCR, western blotting, and immunostaining. Signaling pathways underlying FGF23 effects were assessed by western blotting, and effects of FGF23 on osteogenic markers and phosphate transporters were assessed by real-time reverse transcription-PCR. We detected Klotho and FGFR1 in total aorta but not in vascular smooth muscle cells. FGF23 augmented phosphate-induced vascular calcification in the aortic rings from uremic rats and dose dependently increased ERK1/2 phosphorylation in Klotho-overexpressing but not naive vascular smooth muscle cells. FGF23-induced ERK1/2 phosphorylation was inhibited by SU5402 (FGFR1 inhibitor) and U0126 (MEK inhibitor). FGF23 enhanced phosphate-induced calcification in Klotho-overexpressing vascular smooth muscle cells and increased osteoblastic marker expression, which was inhibited by U0126. In contrast, phosphate transporter expression was not affected by phosphate or FGF23. Thus, FGF23 enhances phosphate-induced vascular calcification by promoting osteoblastic differentiation involving the ERK1/2 pathway.
Assuntos
Doenças da Aorta/induzido quimicamente , Fatores de Crescimento de Fibroblastos/toxicidade , Glucuronidase/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fosfatos/toxicidade , Calcificação Vascular/induzido quimicamente , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/deficiência , Glucuronidase/genética , Proteínas Klotho , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Proteínas Recombinantes/toxicidade , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transfecção , Calcificação Vascular/metabolismo , Calcificação Vascular/patologiaRESUMO
Oxidative stress plays a pivotal role in various pathological conditions, including hypertension, pulmonary hypertension, diabetes, and chronic kidney disease, with high levels of oxidative stress in target organs such as the heart, pancreas, kidney, and lung. Oxidative stress is known to activate multiple intracellular signaling, which induces apoptosis or cell overgrowth, leading to organ dysfunction. As such, targeting oxidative stress is thought to be effective in protecting against organ damage, and measuring oxidative stress status may serve as a biomarker in diverse disease states. Several new intrinsic anti-oxidative or pro-oxidative factors have recently been reported, and are potential new targets. In the present review, we focus on diabetes, pulmonary hypertension, and renal dysfunction, and their relation with new targets - adrenomedullin, oxidized LDL, and mineralocorticoid receptor.
Assuntos
Diabetes Mellitus/metabolismo , Hipertensão/metabolismo , Estresse Oxidativo/fisiologia , Insuficiência Renal Crônica/metabolismo , Animais , Apoptose/fisiologia , Humanos , Espécies Reativas de Oxigênio/metabolismoRESUMO
OBJECTIVE: This study evaluated the non-inferiority of renoprotection afforded by benidipine versus hydrochlorothiazide in hypertensive patients with chronic kidney disease (CKD). METHODS: In this prospective, multicenter, open-labeled, randomized trial, the antialbuminuric effects of benidipine and hydrochlorothiazide were examined in renin-angiotensin system (RAS) inhibitor-treated patients with blood pressure (BP) readings of ≥ 130/80 mmHg and ≤ 180/110 mmHg, a urinary albumin to creatinine ratio (UACR) of ≥ 300 mg/g, and an estimated glomerular filtration rate (eGFR) of ≥ 30 ml/min/1.73m(2). Patients received benidipine (n = 176, final dose: 4.8 mg/day) or hydrochlorothiazide (n = 170, 8.2 mg/day) for 12 months. RESULTS: Benidipine and hydrochlorothiazide exerted similar BP- and eGFR-decreasing actions. The UACR values for benidipine and hydrochlorothiazide were 930.8 (95% confidence interval: 826.1, 1048.7) and 883.1 (781.7, 997.7) mg/g at baseline, respectively. These values were reduced to 790.0 (668.1, 934.2) and 448.5 (372.9, 539.4) mg/g at last observation carried forward (LOCF) visits. The non-inferiority of benidipine versus hydrochlorothiazide was not demonstrated (benidipine/hydrochlorothiazide ratio of LOCF value adjusted for baseline: 1.67 (1.40, 1.99)). CONCLUSIONS: The present study failed to demonstrate the non-inferiority of the antialbuminuric effect of benidipine relative to that of hydrochlorothiazide in RAS inhibitor-treated hypertensive patients with macroalbuminuria.
Assuntos
Di-Hidropiridinas/administração & dosagem , Hidroclorotiazida/administração & dosagem , Hipertensão/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Idoso , Albuminúria/induzido quimicamente , Albuminúria/patologia , Anlodipino/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Hipertensão/complicações , Hipertensão/patologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/patologia , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
BACKGROUND: Adrenomedullin (AM) possesses vasodilative and cell-protective properties. Glycine combines with the C-terminal of AM to form mature, physiologically active AM (mAM). AM is reportedly induced by high glucose condition in vascular endothelial or smooth muscle cells; however, little is known on how AM is activated by amidation. To investigate the behavior of AM in patients undergoing peritoneal dialysis (PD), the concentrations of AM, mAM and CA125 were measured. The mAM to AM ratio (mAM/AM ratio) was also evaluated as a marker of amidation activity. METHODS: Twenty patients were recruited for this study. The effluent at the time of the peritoneal equilibration test was collected and AM, mAM and CA125 concentrations were measured. The expression of AM in peritoneal mesothelial cells (PMCs) collected from effluent was also examined with an indirect immunofluorescent method. RESULTS: Mean values of AM and mAM in effluent were 18.1 ± 1.6 and 4.1 ± 0.3 fmol/mL, respectively. In plasma, they were 42.6 ± 3.3 and 5.6 ± 0.6 fmol/mL, respectively. AM concentrations in effluent did not correlate with plasma AM level but correlated well with the dialysate-to-plasma ratio of creatinine (D/P ratio of creatinine). Moreover, in 7 of 20 cases, concentrations of the mAM and mAM/AM ratio in effluent were higher than in plasma. In effluent, AM concentration but not the mAM/AM ratio correlated with CA125 concentration. Immunocytological study revealed diffuse, cytoplasmic expression of AM in PMCs which were collected from effluent during PD. CONCLUSION: AM is expressed by PMCs and actively amidated in the abdominal cavity of patients undergoing PD.
Assuntos
Adrenomedulina/metabolismo , Soluções para Diálise/uso terapêutico , Epitélio/metabolismo , Diálise Peritoneal , Peritônio/metabolismo , Adrenomedulina/sangue , Biomarcadores/sangue , Biomarcadores/metabolismo , Antígeno Ca-125/metabolismo , Creatinina/sangue , Creatinina/metabolismo , Soluções para Diálise/metabolismo , Feminino , Humanos , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVE: The disaccharide loading test is a method to assess gastric mucosal damage. Since Trelan-G75, which is used for the sugar tolerance test, contains disaccharide maltose, if maltose is detected at a high sensitivity in the sample blood used in the sugar tolerance test, screening for upper gastrointestinal mucosal damage can be made simultaneously with the sugar tolerance test for the diagnosis of diabetes. METHODS: Glucose-6-phosphate is generated by treating maltose with maltose phosphorylase, ß-phosphoglucomutase, and glucose-1,6-bisphosphate. Then, change in the absorbance at 405 nm is measured by the enzymatic cycling method using Thio-NADP, ß-NADPH, and Glucose-6-phosphate dehydrogenase. After evaluating the optimal condition for this method, it is mounted on an automatic biochemical analyzer, and samples after the sugar tolerance test were assayed. RESULTS: Regarding the performance of this method, the repeatability was 10-50 µmol/L with a CV of ≤1.1%. Concerning the assay range, a curve passing the origin with a range of linearity up to 120 µmol/L was obtained. No effect of dyes or sugars in the blood was noted. As a result of application to patients with gastric mucosal disorders (those who had a health checkup), significant differences were observed depending on the stage of atrophic gastritis. DISCUSSION: This method has a high sensitivity and a high precision and can be used for high-speed analysis on an automatic analyzer. It has the potential to be used as a screening test for gastric mucosal damage.
RESUMO
This study aimed to identify factors associated with a strong home blood pressure (BP)-lowering effect of esaxerenone and the incidence of elevated serum potassium levels in hypertensive patients treated with esaxerenone. A pooled analysis of five multicenter, prospective, open-label single-arm studies was conducted, including 479 patients in the full analysis set (FAS) and 492 patients in the safety analysis set. Multivariate linear regression analysis of morning home systolic BP (SBP) and diastolic BP (DBP) changes from baseline to Week 12 in the FAS (primary endpoint) showed that male sex (estimated change 4.37 mmHg), office pulse rate ≥100 beats/min (25.10 mmHg), and calcium channel blocker (CCB) use as a basal antihypertensive agent (4.53 mmHg) were significantly associated with a positive estimated change (weaker BP-lowering effect) in morning home SBP. CCB use (3.70 mmHg) was associated with a positive estimated change in morning home DBP. Urine albumin-to-creatinine ratio 30 to <300 mg/gCr (-4.13 mmHg) was significantly associated with a negative estimated change (stronger BP-lowering effect) in morning home SBP. Based on multivariate logistic regression analysis, elevated baseline serum potassium level (≥4.5 vs < 4.5 mEq/L, odds ratio 13.502) was significantly associated with a high incidence of serum potassium level ≥5.5 mEq/L after esaxerenone treatment. In conclusion, factors associated with a strong BP-lowering effect of esaxerenone were female sex and use of renin-angiotensin system inhibitors as a basal antihypertensive drug. Patients with baseline serum potassium levels ≥4.5 mEq/L had an increased risk of developing elevated serum potassium levels (≥5.5 mEq/L) after esaxerenone treatment.
RESUMO
Inflammation and fibrosis often occur in the kidney after acute injury, resulting in chronic kidney disease and consequent renal failure. Recent studies have indicated that lymphangiogenesis can drive renal inflammation and fibrosis in injured kidneys. However, whether and how this pathogenesis affects the contralateral kidney remain largely unknown. In our study, we uncovered a mechanism by which the contralateral kidney responded to injury. We found that the activation of mineralocorticoid receptors and the increase in vascular endothelial growth factor C in the contralateral kidney after unilateral ureteral obstruction could promote lymphangiogenesis. Furthermore, mineralocorticoid receptor activation in lymphatic endothelial cells resulted in the secretion of myofibroblast markers, thereby contributing to renal fibrosis. We observed that this process could be attenuated by administering the mineralocorticoid receptor blocker eplerenone, which, prevented the development of fibrotic injury in the contralateral kidneys of rats with unilateral ureteral obstruction. These findings offer valuable insights into the intricate mechanisms underlying kidney injury and may have implications for the development of therapeutic strategies to mitigate renal fibrosis in the context of kidney disease.