RESUMO
Renin cells are essential for survival perfected throughout evolution to ensure normal development and defend the organism against a variety of homeostatic threats. During embryonic and early postnatal life, they are progenitors that participate in the morphogenesis of the renal arterial tree. In adult life, they are capable of regenerating injured glomeruli, control blood pressure, fluid-electrolyte balance, tissue perfusion, and in turn, the delivery of oxygen and nutrients to cells. Throughout life, renin cell descendants retain the plasticity or memory to regain the renin phenotype when homeostasis is threatened. To perform all of these functions and maintain well-being, renin cells must regulate their identity and fate. Here, we review the major mechanisms that control the differentiation and fate of renin cells, the chromatin events that control the memory of the renin phenotype, and the major pathways that determine their plasticity. We also examine how chronic stimulation of renin cells alters their fate leading to the development of a severe and concentric hypertrophy of the intrarenal arteries and arterioles. Lastly, we provide examples of additional changes in renin cell fate that contribute to equally severe kidney disorders.
Assuntos
Hipertensão/etiologia , Rim/citologia , Renina/fisiologia , Animais , Arteríolas/embriologia , Pressão Sanguínea/fisiologia , Comunicação Celular , Diferenciação Celular , Plasticidade Celular , Cromatina/fisiologia , Montagem e Desmontagem da Cromatina/fisiologia , Conexinas/fisiologia , Homeostase , Humanos , Integrinas/fisiologia , Sistema Justaglomerular/citologia , Rim/irrigação sanguínea , Rim/embriologia , Glomérulos Renais/fisiologia , Camundongos , MicroRNAs/fisiologia , Fenótipo , Regeneração/fisiologia , Artéria Renal , Renina/metabolismo , Sistema Renina-Angiotensina/fisiologia , Células-Tronco/fisiologia , Equilíbrio HidroeletrolíticoRESUMO
The renin-angiotensin system (RAS) is widely recognized as one of the most important vasoactive hormonal systems in the physiological regulation of blood pressure and the development of hypertension. This recognition is derived from, and supported by, extensive molecular, cellular, genetic, and pharmacological studies on the circulating (tissue-to-tissue), paracrine (cell-to-cell), and intracrine (intracellular, mitochondrial, nuclear) RAS during last several decades. Now, it is widely accepted that circulating and local RAS may act independently or interactively, to regulate sympathetic activity, systemic and renal hemodynamics, body salt and fluid balance, and blood pressure homeostasis. However, there remains continuous debate with respect to the specific sources of intratubular and intracellular RAS in the kidney and other tissues, the relative contributions of the circulating RAS to intratubular and intracellular RAS, and the roles of intratubular compared with intracellular RAS to the normal control of blood pressure or the development of angiotensin II (ANG II)-dependent hypertension. Based on a lecture given at the recent XI International Symposium on Vasoactive Peptides held in Horizonte, Brazil, this article reviews recent studies using mouse models with global, kidney- or proximal tubule-specific overexpression (knockin) or deletion (knockout) of components of the RAS or its receptors. Although much knowledge has been gained from cell- and tissue-specific transgenic or knockout models, a unifying and integrative approach is now required to better understand how the circulating and local intratubular/intracellular RAS act independently, or with other vasoactive systems, to regulate blood pressure, cardiovascular and kidney function.
Assuntos
Pressão Sanguínea/fisiologia , Rim/metabolismo , Sistema Renina-Angiotensina/fisiologia , Angiotensina II/fisiologia , Angiotensinogênio/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Rim/fisiologia , Túbulos Renais Proximais/metabolismo , Fígado/metabolismo , Camundongos , Renina/fisiologiaRESUMO
BACKGROUND: Low-renin levels in Blacks have been associated with volume-loading hypertension (HT). Depression symptoms, frequently co-occurring with vascular dysregulation, might reflect a disturbed renin-angiotensin-aldosterone-system (RAAS). We aimed to assess prospective changes (∆) in depression symptoms, RAAS (renin, aldosterone), diastolic blood pressure (DBP), and estimated glomerular filtration rate (eGFR) in a bi-ethnic sex cohort. METHODS: We included 195 Black and White teachers (43.7⯱â¯9â¯years) from a South African 3-year prospective study. Hypertension medication users, diabetics and human immunodeficiency virus infected individuals were excluded. Depression symptoms (Patient-Health-Questionnaire-9/PHQ-9), 24â¯h blood pressure measurements and fasting blood samples were obtained. RESULTS: Blacks had lower renin but higher DBP and eGFR levels at baseline (pâ¯≤â¯.01) when compared to Whites. Blacks and Whites with depression (PHQ-9â¯≥â¯10) at baseline developed co-morbidity for having both depression plus DBP-HT at follow-up (Blacks, 49.1%; Whites, 13.1%). At 3-year follow-up, chronic depression symptoms were related to chronic lower renin in Blacks [Adjusted R2 0.20; ß -0.37 (-0.66, -0.08), pâ¯=â¯.02]. Chronic depression symptoms also predicted DBP hypertension in Blacks [ROC AUCâ¯=â¯0.61 (0.48-0.75); sensitivity/specificity 78.1/46.3%]. No prospective associations existed between depression symptoms, aldosterone and eGFR. CONCLUSION: Chronic depression symptoms in Blacks activated the RAAS system activity with apparent desensitization of renin activity. Chronic depression could be causal to hypertension and in turn, lowers renin activity as a protective mechanism against volume-loading. These findings emphasize the potential impact of depression on the low renin-hypertension phenotype in Blacks in terms of diagnosis and treatment.
Assuntos
População Negra , Depressão/epidemiologia , Depressão/fisiopatologia , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Sistema Renina-Angiotensina/fisiologia , Renina/fisiologia , Adulto , Aldosterona/sangue , Pressão Sanguínea , Depressão/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Renina/sangue , África do Sul/epidemiologia , População BrancaRESUMO
Plasma prorenin is commonly elevated in diabetic patients and appears to predict the development of diabetic nephropathy. However, the pathological role of prorenin is unclear. In the present study, a transgenic, inducible, hepatic prorenin-overexpressing rat model was generated and the effect of prorenin in organ injury was examined. Four groups of rats (cyp1a1 prorenin transgenic male and female rats and non-transgenic littermates) were assigned to receive a diet containing 0.3% of the transgene inducer indole-3-carbinol (I3C) for 4 weeks. Plasma prorenin concentration was increased and mean arterial pressure (MAP) increased from 80 ± 18 to 138 ± 17 (mmHg), whereas renal prorenin/renin protein expression was unchanged, in transgenic rats fed with I3C diet. The intact prorenin, not renin, in plasma and urine samples was further observed by Western blot analysis. Importantly, transgenic rats with high levels of prorenin developed albuminuria, glomerular and tubulointerstitial fibrosis associated with increased expression of transforming growth factor ß (TGFß) 1 (TGFß1), plasminogen activator inhibitor-1 (PAI-1), collagen, and fibronectin (FN). These rats also exhibited cardiac hypertrophy determined by echocardiography, with elevated ratio of heart weight to body weight (HW/BW). Cardiac collagen in interstitial and perivascular regions was prominent, accompanied by the increase in mRNA contents of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), ß-myosin heavy chain (ß-MHC), TGFß1, PAI-1, and collagen in the heart tissue. Furthermore, renal protein levels of p-NF-κB-p65 and monocyte chemoattractant protein-1 (MCP-1), NAPDH oxidases, malondialdehyde (MDA) and 8-isoprostane (8-IP), p-ERK, p-ß-catenin, and p-Akt were dramatically increased in prorenin overexpressing rats. These results indicate that prorenin, without being converted into renin, causes hypertension, renal and cardiac fibrosis via the induction of inflammation, oxidative stress and the ERK, ß-catenin, and Akt-mediated signals.
Assuntos
Hipertensão/fisiopatologia , Rim/patologia , Miocárdio/patologia , Renina/fisiologia , Albuminúria/sangue , Albuminúria/fisiopatologia , Animais , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/fisiopatologia , Ecocardiografia , Feminino , Fibrose , Expressão Gênica , Hipertensão/sangue , Masculino , Miocárdio/metabolismo , Tamanho do Órgão , Estresse Oxidativo/fisiologia , Ratos Transgênicos , Renina/sangue , Renina/genética , Transdução de Sinais/fisiologiaRESUMO
OBJECTIVES: This study examined the association of aldosterone and plasma renin activity (PRA) with incident cardiovascular disease (CVD), using a composite endpoint of coronary heart disease, stroke, and/or heart failure and mortality among African Americans in the Jackson Heart Study. BACKGROUND: There is a paucity of data for the association of aldosterone and PRA with incident CVD or all-cause mortality among community-dwelling African Americans. METHODS: A total of 4,985 African American adults, 21 to 94 years of age, were followed for 12 years. Aldosterone, PRA, and cardiovascular risk factors were collected at baseline (from 2000 to 2004). Incident events included coronary heart disease and stroke (assessed from 2000 to 2011) and heart failure (assessed from 2005 to 2011). Cox models were used to estimate hazard ratios (HRs) for incident CVD and mortality, adjusting for age, sex, education, occupation, current smoking, physical activity, dietary intake, and body mass index. RESULTS: Among 4,160 participants without prevalent CVD over a median follow-up of 7 years, there were 322 incident CVD cases. In adjusted analyses, each 1-U SD increase in log-aldosterone and log-PRA were associated with HR of 1.26 (95% confidence intervals [CI]: 1.14 to 1.40) and 1.16 (95% CI: 1.02 to 1.33) for incident CVD, respectively. Over a median of 8 years, 513 deaths occurred among 4,985 participants. In adjusted analyses, each 1-U SD increase in log-aldosterone and log-PRA were associated with HRs of 1.13 (95% CI: 1.04 to 1.23) and 1.12 (95% CI: 1.01 to 1.24) for mortality, respectively. CONCLUSIONS: Elevated aldosterone and PRA may play a significant role in the development of CVD and all-cause mortality among African Americans.
Assuntos
Aldosterona/fisiologia , Doenças Cardiovasculares/mortalidade , Renina/fisiologia , Adulto , Negro ou Afro-Americano/etnologia , Idoso , Idoso de 80 Anos ou mais , Aldosterona/metabolismo , Índice de Massa Corporal , Doenças Cardiovasculares/etnologia , Causas de Morte , Doença das Coronárias/etnologia , Doença das Coronárias/mortalidade , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etnologia , Infarto do Miocárdio/mortalidade , Estudos Prospectivos , Renina/metabolismo , Fatores de Risco , Acidente Vascular Cerebral/etnologia , Acidente Vascular Cerebral/mortalidade , Estados Unidos/epidemiologia , Adulto JovemRESUMO
During development, renin cells are precursors for arteriolar smooth muscle, mesangial cells, and interstitial pericytes. Those seemingly differentiated descendants retain the memory to re-express renin when there is a threat to homeostasis. Understanding how such molecular memory is constructed and regulated would be crucial to comprehend cell identity which is, in turn, intimately linked to homeostasis.
Assuntos
Plasticidade Celular , Homeostase/fisiologia , Sistema Justaglomerular/citologia , Rim/irrigação sanguínea , Renina/fisiologia , Animais , Humanos , Sistema Justaglomerular/fisiologiaRESUMO
Renin substrate, biological renin activity, and/or renin-secreting cells in kidneys evolved at an early stage of vertebrate phylogeny. Angiotensin (Ang) I and II molecules have been identified biochemically in representative species of all vertebrate classes, although variation occurs in amino acids at positions 1, 5, and 9 of Ang I. Variations have also evolved in amino acid positions 3 and 4 in some cartilaginous fish. Angiotensin receptors, AT1 and AT2 homologues, have been identified molecularly or characterized pharmacologically in nonmammalian vertebrates. Also, various forms of angiotensins that bypass the traditional renin-angiotensin system (RAS) cascades or those from large peptide substrates, particularly in tissues, are present. Nonetheless, the phylogenetically important functions of RAS are to maintain blood pressure/blood volume homeostasis and ion-fluid balance via the kidney and central mechanisms. Stimulation of cell growth and vascularization, possibly via paracrine action of angiotensins, and the molecular biology of RAS and its receptors have been intensive research foci. This review provides an overview of: (1) the phylogenetic appearance, structure, and biochemistry of the RAS cascade; (2) the properties of angiotensin receptors from comparative viewpoints; and (3) the functions and regulation of the RAS in nonmammalian vertebrates. Discussions focus on the most fundamental functions of the RAS that have been conserved throughout phylogenetic advancement, as well as on their physiological implications and significance. Examining the biological history of RAS will help us analyze the complex RAS systems of mammals. Furthermore, suitable models for answering specific questions are often found in more primitive animals.
Assuntos
Rim/anatomia & histologia , Rim/fisiologia , Sistema Renina-Angiotensina/fisiologia , Angiotensinas/fisiologia , Animais , Humanos , Filogenia , Renina/fisiologia , VertebradosRESUMO
Pathophysiological mechanisms underlying the development of renal dysfunction and progression of congestive heart failure (CHF) remain poorly understood. Recent studies have revealed striking differences in the role of epoxyeicosatrienoic acids (EETs), active products of cytochrome P-450-dependent epoxygenase pathway of arachidonic acid, in the progression of aorto-caval fistula (ACF)-induced CHF between hypertensive Ren-2 renin transgenic rats (TGR) and transgene-negative normotensive Hannover Sprague-Dawley (HanSD) controls. Both ACF TGR and ACF HanSD strains exhibited marked intrarenal EETs deficiency and impairment of renal function, and in both strains chronic pharmacologic inhibition of soluble epoxide hydrolase (sEH) (which normally degrades EETs) normalized EETs levels. However, the treatment improved the survival rate and attenuated renal function impairment in ACF TGR only. Here we aimed to establish if the reported improved renal function and attenuation of progression of CHF in ACF TGR observed after she blockade depends on increased vasodilatory responsiveness of renal resistance arteries to EETs. Therefore, we examined the responses of interlobar arteries from kidneys of ACF TGR and ACF HanSD rats to EET-A, a new stable 14,15-EET analog. We found that the arteries from ACF HanSD kidneys rats exhibited greater vasodilator responses when compared to the ACF TGR arteries. Hence, reduced renal vasodilatory responsiveness cannot be responsible for the lack of beneficial effects of chronic sEH inhibition on the development of renal dysfunction and progression of CHF in ACF HanSD rats.
Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Insuficiência Cardíaca/fisiopatologia , Hipertensão/fisiopatologia , Rim/irrigação sanguínea , Renina/fisiologia , Vasodilatação/fisiologia , Ácido 8,11,14-Eicosatrienoico/química , Ácido 8,11,14-Eicosatrienoico/farmacologia , Acetilcolina/farmacologia , Animais , Progressão da Doença , Relação Dose-Resposta a Droga , Insuficiência Cardíaca/genética , Hipertensão/genética , Rim/efeitos dos fármacos , Rim/fisiologia , Masculino , Norepinefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Circulação Renal/efeitos dos fármacos , Circulação Renal/fisiologia , Vasodilatação/efeitos dos fármacosRESUMO
Collecting duct (CD)-derived renin is involved in the hypertensive response to chronic angiotensin-II (Ang-II) administration. However, whether CD renin is involved in Ang-II independent hypertension is currently unknown. To begin to examine this, 12 week old male and female CD-specific renin knock out (KO) mice and their littermate controls were subjected to uni-nephrectomy followed by 2 weeks of deoxycorticosterone acetate (DOCA) infusion combined with a high salt diet. Radiotelemetric blood pressure (BP) was similar between KO and control mice at baseline; BP increased in both groups to a similar degree throughout the 2 weeks of DOCA-salt treatment. Urinary albumin excretion and plasma blood urea nitrogen were comparable between the two groups after DOCA-salt treatment. Fibrosis as assessed by Masson's Trichrome stain/Sirius Red stain and collagen-1 mRNA expression was similar between control and KO mice. Compared to baseline, DOCA-salt treatment decreased plasma renin concentration (PRC), urinary renin excretion and medullary renin mRNA expression in both floxed and CD renin KO mice with no detectable differences between the two groups. Further, in primary culture of rat inner medullary CD, aldosterone treatment did not change renin activity or total renin content. Taken together, these data suggest that CD derived renin does not play a role in DOCA-salt hypertension.
Assuntos
Acetato de Desoxicorticosterona/antagonistas & inibidores , Hipertensão/fisiopatologia , Túbulos Renais Coletores/metabolismo , Rim/lesões , Renina/fisiologia , Animais , Pressão Sanguínea , Células Cultivadas , Hipertensão/induzido quimicamente , Medula Renal/metabolismo , Masculino , Camundongos , Camundongos Knockout , RNA Mensageiro/genética , Ratos Sprague-Dawley , Renina/genética , Renina/urinaRESUMO
Because adult podocytes cannot proliferate and are therefore unable to self-renew, replacement of these cells depends on stem/progenitor cells. Although podocyte number is higher after renin-angiotensin-aldosterone system (RAAS) inhibition in glomerular diseases, the events explaining this increase are unclear. Cells of renin lineage (CoRL) have marked plasticity, including the ability to acquire a podocyte phenotype. To test the hypothesis that RAAS inhibition partially replenishes adult podocytes by increasing CoRL number, migration, and/or transdifferentiation, we administered tamoxifen to Ren1cCreERxRs-tdTomato-R CoRL reporter mice to induce permanent labeling of CoRL with red fluorescent protein variant tdTomato. We then induced experimental FSGS, typified by abrupt podocyte depletion, with a cytopathic antipodocyte antibody. RAAS inhibition by enalapril (angiotensin-converting enzyme inhibitor) or losartan (angiotensin-receptor blocker) in FSGS mice stimulated the proliferation of CoRL, increasing the reservoir of these cells in the juxtaglomerular compartment (JGC). Compared with water or hydralazine, RAAS inhibition significantly increased the migration of CoRL from the JGC to the intraglomerular compartment (IGC), with more glomeruli containing RFP+CoRL and, within these glomeruli, more RFP+CoRL. Moreover, RAAS inhibition in FSGS mice increased RFP+CoRL transdifferentiation in the IGC to phenotypes, consistent with those of podocytes (coexpression of synaptopodin and Wilms tumor protein), parietal epithelial cells (PAX 8), and mesangial cells (α8 integrin). These results show that in the context of podocyte depletion in FSGS, RAAS inhibition augments CoRL proliferation and plasticity toward three different glomerular cell lineages.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Linhagem da Célula , Enalapril/farmacologia , Losartan/farmacologia , Podócitos/citologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Renina/fisiologia , Animais , Linhagem da Célula/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Masculino , Camundongos , Podócitos/efeitos dos fármacosRESUMO
AIMS: Chronic endothelin receptor A (ETA) blockade lowered blood pressure (BP) by decreasing angiotensin-dependent vasoconstriction and attenuating calcium influx. We tested whether the addition of ETA blockade to renin-angiotensin system (RAS) blockade would have further effects on the principal vasoactive systems contributing to BP maintenance in Ren-2 transgenic rats (TGR). METHODS: Four-week-old TGR rats were fed with normal-salt diet and given either different renin-angiotensin system (RAS) blockers [angiotensin receptor blocker losartan, angiotensin converting enzyme inhibitor captopril, direct renin inhibitor aliskiren], or ETA blocker (atrasentan) alone, or a combination of atrasentan with RAS blockers for 4weeks. At the end of the study, basal BP and acute BP responses to sequential blockade of renin-angiotensin (RAS), sympathetic nervous (SNS), and nitric oxide (NO) systems were determined in conscious rats. Thereafter, BP responses to acute inhibition of nifedipine-sensitive calcium influx through voltage-dependent calcium channels (L-VDCC) were measured. KEY FINDINGS: All RAS blockers similarly decreased BP to normotension, their effects being mediated through substantially attenuated RAS-dependent and moderately decreased SNS-dependent vasoconstriction. Atrasentan alone partially lowered BP, while BP was normalized by combination of atrasentan with either RAS blocker. In combination therapies, BP lowering effects resulted from the attenuation of both RAS- and SNS-dependent vasoconstriction. Moreover, atrasentan-treated groups had substantially reduced NO-dependent vasodilation and significantly decreased calcium influx through L-VDCC. CONCLUSIONS: Although the BP-lowering effect of combined ETA and RAS blockades in TGR is predominantly dependent on the effects exerted by RAS blockade, further effects are attributable to decreased calcium influx due to chronic ETA blockade.
Assuntos
Antagonistas dos Receptores de Endotelina/farmacologia , Receptor de Endotelina A/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Renina/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Renina/genéticaRESUMO
BACKGROUND: Reninoma is an extremely rare renal tumor characterized by excessive renin secretion causing secondary hypertension and hypokalemia. Reninoma is a benign and highly manageable lesion if it is discovered early and removed surgically. METHODS: We report six cases of reninoma and provide a literature review on this rare disease, highlighting the diagnostic evaluation and follow-up of each patient. RESULTS AND CONCLUSIONS: Reninoma should be considered in young adults with elevated renin activity and refractory hypertension. Imaging studies and selective venous catheterization are often helpful in identifying the lesion. In most cases of reninoma presenting with renin-mediated hypertension, conservative surgical treatment should be considered to remove the small, superficial lesion.
Assuntos
Hipertensão/fisiopatologia , Renina/fisiologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto JovemRESUMO
The intrarenal renin-angiotensin system (RAS) plays a critical role in the pathogenesis and progression of hypertension and kidney disease. In angiotensin (Ang) II-dependent hypertension, collecting duct renin synthesis and secretion are stimulated despite suppression of juxtaglomerular (JG) renin. This effect is mediated by the AngII type I receptor (AT1 R), independent of blood pressure. Although the regulation of JG renin has been extensively studied, the mechanisms by which renin is regulated in the collecting duct remain unclear. The augmentation of renin synthesis and activity in the collecting duct may provide a pathway for additional generation of intrarenal and intratubular AngII formation due to the presence of angiotensinogen substrate and angiotensin-converting enzyme in the nephron. The recently described (pro)renin receptor ((P)RR) binds renin or prorenin, enhancing renin activity and fully activating the biologically inactive prorenin peptide. Stimulation of (P)RR also activates intracellular pathways related to fibrosis. Renin and the (P)RR are augmented in renal tissues of AngII-dependent hypertensive rats. However, the functional contribution of the (P)RR to enhanced renin activity in the collecting duct and its contribution to the development of hypertension and kidney disease have not been well elucidated. This review focuses on recent evidence demonstrating the mechanism of renin regulation in the collecting ducts and its interaction with the (P)RR. The data suggest that renin-(P)RR interactions may induce stimulation of intracellular pathways associated with the development of hypertension and kidney disease.
Assuntos
Hipertensão/fisiopatologia , Túbulos Renais Coletores/fisiopatologia , Receptores de Superfície Celular/fisiologia , ATPases Vacuolares Próton-Translocadoras/fisiologia , Animais , Humanos , Hipertensão/diagnóstico , Renina/fisiologia , Sistema Renina-Angiotensina/fisiologiaRESUMO
Mesangial cell injury has a major role in many CKDs. Because renin-positive precursor cells give rise to mesangial cells during nephrogenesis, this study tested the hypothesis that the same phenomenon contributes to glomerular regeneration after murine experimental mesangial injury. Mesangiolysis was induced by administration of an anti-mesangial cell serum in combination with LPS. In enhanced green fluorescent protein-reporter mice with constitutively labeled renin lineage cells, the size of the enhanced green fluorescent protein-positive area in the glomerular tufts increased after mesangial injury. Furthermore, we generated a novel Tet-on inducible triple-transgenic LacZ reporter line that allowed selective labeling of renin cells along renal afferent arterioles of adult mice. Although no intraglomerular LacZ expression was detected in healthy mice, about two-thirds of the glomerular tufts became LacZ positive during the regenerative phase after severe mesangial injury. Intraglomerular renin descendant LacZ-expressing cells colocalized with mesangial cell markers α8-integrin and PDGF receptor-ß but not with endothelial, podocyte, or parietal epithelial cell markers. In contrast with LacZ-positive cells in the afferent arterioles, LacZ-positive cells in the glomerular tuft did not express renin. These data demonstrate that extraglomerular renin lineage cells represent a major source of repopulating cells for reconstitution of the intraglomerular mesangium after injury.
Assuntos
Linhagem da Célula , Mesângio Glomerular/metabolismo , Rim/lesões , Renina/fisiologia , Animais , Animais Geneticamente Modificados , Doxiciclina/administração & dosagem , Enalapril/administração & dosagem , Feminino , Genes Reporter , Proteínas de Fluorescência Verde/metabolismo , Imageamento Tridimensional , Glomérulos Renais/metabolismo , Óperon Lac , Lipopolissacarídeos/química , Masculino , Camundongos , Camundongos Transgênicos , Renina/metabolismo , Células-Tronco/citologiaRESUMO
BACKGROUND: Right ventricular dysfunction (RVD) is associated with poor cardiovascular outcome. The renin-angiotensin-aldosterone system is involved in alterations of the left ventricular geometry and function. Detrimental effects of the renin-angiotensin-aldosterone system on the right ventricular function are being postulated, but data supporting this assumption are still lacking. The aim of the study was to assess the impact of hyperreninemia, hyperaldosteronism or their combination on right ventricular function in hypertensive individuals. METHODS: Plasma renin activity (PRA) and plasma aldosterone concentrations (PACs) were measured in 116 hypertensive patients, divided as follows: normal PRA and PAC (nâ=â38); high PRA and normal PAC (hypereninemia) (nâ=â26); normal PRA and high PAC (hyperaldosternism) (nâ=â27); high PRA and PAC (HRA) (nâ=â25). Echocardiographic evaluation of the left and right ventricles (RV), including tissue Doppler imaging, was performed. RVD was identified by tissue Doppler Imaging-derived Myocardial Performance Index, calculated with a multisegmental approach. RESULTS: Indices of the right ventricular structure and function, as well as the prevalence of RVD, were higher in hyperreninemia and hyperaldosternism groups as compared with the normal group, and a further increase was observed in the HRA patients. Regression models showed a similar risk of RVD in the hyperreninemia and hyperaldosternism patients, regardless of systemic and pulmonary pressure, as well as left ventricular dysfunction. Notably, patients with both hyperreninemia and hyperaldosternism exhibited the strongest association with RVD as compared with patients with only hyperreninemia or hyperaldosternism. CONCLUSIONS: Isolated hyperreninemia or hyperaldosternism determines a similar impairment of the right ventricular function, whereas their combination is further detrimental. Renin and aldosterone may represent early biomarkers of right ventricular dysfunction in hypertension.
Assuntos
Aldosterona/fisiologia , Hipertensão/fisiopatologia , Sistema Renina-Angiotensina/fisiologia , Renina/fisiologia , Função Ventricular Direita/fisiologia , Adulto , Aldosterona/sangue , Antropometria/métodos , Biomarcadores/sangue , Ecocardiografia Doppler/métodos , Feminino , Ventrículos do Coração/patologia , Humanos , Hipertensão/sangue , Hipertensão/complicações , Hipertensão/patologia , Masculino , Pessoa de Meia-Idade , Renina/sangue , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/patologia , Disfunção Ventricular Direita/fisiopatologiaRESUMO
BACKGROUND: Aldosterone synthase inhibition provides the potential to attenuate both the mineralocorticoid receptor-dependent and independent actions of aldosterone. In vitro studies with recombinant human enzymes showed LCI699 to be a potent, reversible, competitive inhibitor of aldosterone synthase (K i = 1.4 ± 0.2 nmol/L in humans) with relative selectivity over 11ß-hydroxylase. METHODS: Hormonal effects of orally administered LCI699 were examined in rat and monkey in vivo models of adrenocorticotropic hormone (ACTH) and angiotensin-II-stimulated aldosterone release, and were compared with the mineralocorticoid receptor antagonist eplerenone in a randomized, placebo-controlled study conducted in 99 healthy human subjects. The effects of LCI699 and eplerenone on cardiac and renal sequelae of aldosterone excess were investigated in a double-transgenic rat (dTG rat) model overexpressing human renin and angiotensinogen. RESULTS: Rat and monkey in vivo models of stimulated aldosterone release predicted human dose- and exposure-response relationships, but overestimated the selectivity of LCI699 in humans. In the dTG rat model, LCI699 dose-dependently blocked increases in aldosterone, prevented development of cardiac and renal functional abnormalities independent of blood pressure changes, and prolonged survival. Eplerenone prolonged survival to a similar extent, but was less effective in preventing cardiac and renal damage. In healthy human subjects, LCI699 0.5 mg selectively reduced plasma and 24 h urinary aldosterone by 49 ± 3% and 39 ± 6% respectively (Day 1, mean ± SEM; P < 0.001 vs placebo), which was associated with natriuresis and an increase in plasma renin activity. Doses of LCI699 greater than 1 mg inhibited basal and ACTH-stimulated cortisol. Eplerenone 100 mg increased plasma and 24 h urinary aldosterone while stimulating natriuresis and increasing renin activity. In contrast to eplerenone, LCI699 increased the aldosterone precursor 11-deoxycorticosterone and urinary potassium excretion. CONCLUSIONS: These results provide new insights into the cardiac and renal effects of inhibiting aldosterone synthase in experimental models and translation of the hormonal effects to humans. Selective inhibition of aldosterone synthase appears to be a promising approach to treat diseases associated with aldosterone excess.
Assuntos
Angiotensinogênio/fisiologia , Citocromo P-450 CYP11B2/antagonistas & inibidores , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Renina/fisiologia , Pesquisa Translacional Biomédica , Animais , Método Duplo-Cego , Eplerenona , Haplorrinos , Coração/fisiopatologia , Humanos , Imidazóis/farmacologia , Rim/fisiopatologia , Masculino , Placebos , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Espironolactona/análogos & derivados , Espironolactona/farmacologiaRESUMO
The renin-angiotensin system has powerful effects in control of the blood pressure and sodium homeostasis. These actions are coordinated through integrated actions in the kidney, cardiovascular system and the central nervous system. Along with its impact on blood pressure, the renin-angiotensin system also influences a range of processes from inflammation and immune responses to longevity. Here, we review the actions of the "classical" renin-angiotensin system, whereby the substrate protein angiotensinogen is processed in a two-step reaction by renin and angiotensin converting enzyme, resulting in the sequential generation of angiotensin I and angiotensin II, the major biologically active renin-angiotensin system peptide, which exerts its actions via type 1 and type 2 angiotensin receptors. In recent years, several new enzymes, peptides, and receptors related to the renin-angiotensin system have been identified, manifesting a complexity that was previously unappreciated. While the functions of these alternative pathways will be reviewed elsewhere in this journal, our focus here is on the physiological role of components of the "classical" renin-angiotensin system, with an emphasis on new developments and modern concepts.
Assuntos
Rim/fisiologia , Sistema Renina-Angiotensina/fisiologia , Angiotensinogênio/fisiologia , Animais , Humanos , Peptidil Dipeptidase A/fisiologia , Renina/fisiologiaRESUMO
Bilateral renal denervation (BRD) has been shown to reduce hypertension and improve renal function in both human and experimental studies. We hypothesized that chronic intervention with BRD may also attenuate renal injury and fibrosis in diabetic nephropathy. This hypothesis was examined in a female streptozotocin-induced diabetic (mRen-2)27 rat (TGR) shown to capture the cardinal features of human diabetic nephropathy. Following diabetic induction, BRD/sham surgeries were conducted repeatedly (at the week 3, 6, and 9 following induction) in both diabetic and normoglycemic animals. Renal denervation resulted in a progressive decrease in systolic blood pressure from first denervation to termination (at 12 wk post-diabetic induction) in both normoglycemic and diabetic rats. Renal norepinephrine content was significantly raised following diabetic induction and ablated in denervated normoglycemic and diabetic groups. A significant increase in glomerular basement membrane thickening and mesangial expansion was seen in the diabetic kidneys; this morphological appearance was markedly reduced by BRD. Immunohistochemistry and protein densitometric analysis of diabetic innervated kidneys confirmed the presence of significantly increased levels of collagens I and IV, α-smooth muscle actin, the ANG II type 1 receptor, and transforming growth factor-ß. Renal denervation significantly reduced protein expression of these fibrotic markers. Furthermore, BRD attenuated albuminuria and prevented the loss of glomerular podocin expression in these diabetic animals. In conclusion, BRD decreases systolic blood pressure and reduces the development of renal fibrosis, glomerulosclerosis, and albuminuria in this model of diabetic nephropathy. The evidence presented strongly suggests that renal denervation may serve as a therapeutic intervention to attenuate the progression of renal injury in diabetic nephropathy.
Assuntos
Injúria Renal Aguda/prevenção & controle , Denervação/métodos , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/complicações , Rim/inervação , Renina/genética , Injúria Renal Aguda/patologia , Injúria Renal Aguda/fisiopatologia , Animais , Membrana Basal/patologia , Diabetes Mellitus Experimental/induzido quimicamente , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Fibrose , Heterozigoto , Glomérulos Renais/patologia , Ratos , Ratos Transgênicos , Renina/fisiologia , Estreptozocina/efeitos adversosRESUMO
Among the components of the renin-angiotensin-aldosterone (RAAS) system, which controls blood pressure as well as fluid and electrolyte balance, renin, angiotensin II and its receptors AT1/2, and aldosterone and the mineralocorticoid receptor have been exploited as targets of drug development. Accumulating evidence suggests that the RAAS is linked, through a systemic/endocrine as well as a local loop, to inflammation, oxidative stress, cardiovascular and renal injury, and calcium and bone metabolism.
Assuntos
Osso e Ossos/metabolismo , Sistema Renina-Angiotensina/fisiologia , Injúria Renal Aguda/genética , Aldosterona/fisiologia , Angiotensina II/fisiologia , Animais , Cálcio/metabolismo , Doenças Cardiovasculares/genética , Descoberta de Drogas , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Inflamação/genética , Terapia de Alvo Molecular , Osteoporose/tratamento farmacológico , Osteoporose/genética , Estresse Oxidativo/genética , Receptor Tipo 1 de Angiotensina/fisiologia , Receptor Tipo 2 de Angiotensina/fisiologia , Receptores de Mineralocorticoides/fisiologia , Renina/fisiologiaRESUMO
The circadian timing system is critically involved in the maintenance of fluid and electrolyte balance and BP control. However, the role of peripheral circadian clocks in these homeostatic mechanisms remains unknown. We addressed this question in a mouse model carrying a conditional allele of the circadian clock gene Bmal1 and expressing Cre recombinase under the endogenous Renin promoter (Bmal1(lox/lox)/Ren1(d)Cre mice). Analysis of Bmal1(lox/lox)/Ren1(d)Cre mice showed that the floxed Bmal1 allele was excised in the kidney. In the kidney, BMAL1 protein expression was absent in the renin-secreting granular cells of the juxtaglomerular apparatus and the collecting duct. A partial reduction of BMAL1 expression was observed in the medullary thick ascending limb. Functional analyses showed that Bmal1(lox/lox)/Ren1(d)Cre mice exhibited multiple abnormalities, including increased urine volume, changes in the circadian rhythm of urinary sodium excretion, increased GFR, and significantly reduced plasma aldosterone levels. These changes were accompanied by a reduction in BP. These results show that local renal circadian clocks control body fluid and BP homeostasis.