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1.
Am J Physiol Renal Physiol ; 321(3): F378-F388, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34338032

RESUMO

Developmentally heterogeneous renin-expressing cells serve as progenitors for mural, glomerular, and tubular cells during nephrogenesis and are collectively termed renin lineage cells (RLCs). In this study, we quantified different renal vascular and tubular cell types based on specific markers and assessed proliferation and de novo differentiation in the RLC population. We used kidney sections of mRenCre-mT/mG mice throughout nephrogenesis. Marker positivity was evaluated in whole digitalized sections. At embryonic day 16, RLCs appeared in the developing kidney, and the expression of all stained markers in RLCs was observed. The proliferation rate of RLCs did not differ from the proliferation rate of non-RLCs. RLCs expanded mainly by de novo differentiation (neogenesis). Fractions of RLCs originating from the stromal progenitors of the metanephric mesenchyme (renin-producing cells, vascular smooth muscle cells, and mesangial cells) decreased during nephrogenesis. In contrast, aquaporin-2-positive RLCs in the collecting duct system, which embryonically emerges almost exclusively from the ureteric bud, expanded postpartum. The cubilin-positive RLC fraction in the proximal tubule, deriving from the cap mesenchyme, remained constant. In summary, RLCs were continuously detectable in the vascular and tubular compartments of the kidney during nephrogenesis. Therein, various patterns of RLC differentiation that depend on the embryonic origin of the cells were identified.NEW & NOTEWORTHY The unifying feature of the renal renin lineage cells (RLCs) is their origin from renin-expressing progenitors. RLCs evolve to an embryologically heterogeneous large population in structures with different ancestry. RLCs are also targets for the widely used renin-angiotensin-system blockers, which modulate their phenotype. Unveiling the different differentiation patterns of RLCs in the developing kidney contributes to understanding changes in their cell fate in response to homeostatic challenges and the use of antihypertensive drugs.


Assuntos
Diferenciação Celular/fisiologia , Glomérulos Renais/metabolismo , Rim/metabolismo , Células Mesangiais/metabolismo , Renina/metabolismo , Animais , Linhagem da Célula/fisiologia , Mesoderma/metabolismo , Camundongos , Células-Tronco/metabolismo
2.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281199

RESUMO

The current global prevalence of heart failure is estimated at 64.34 million cases, and it is expected to increase in the coming years, especially in countries with a medium-low sociodemographic index where the prevalence of risk factors is increasing alarmingly. Heart failure is associated with many comorbidities and among them, cancer has stood out as a contributor of death in these patients. This connection points out new challenges both in the context of the pathophysiological mechanisms involved, as well as in the quality of life of affected individuals. A hallmark of heart failure is chronic activation of the renin-angiotensin-aldosterone system, especially marked by a systemic increase in levels of angiotensin-II, a peptide with pleiotropic activities. Drugs that target the renin-angiotensin-aldosterone system have shown promising results both in the prevention of secondary cardiovascular events in myocardial infarction and heart failure, including a lower risk of certain cancers in these patients, as well as in current cancer therapies; therefore, understanding the mechanisms involved in this complex relationship will provide tools for a better diagnosis and treatment and to improve the prognosis and quality of life of people suffering from these two deadly diseases.


Assuntos
Isquemia Miocárdica/fisiopatologia , Neoplasias/fisiopatologia , Sistema Renina-Angiotensina/fisiologia , Aldosterona/metabolismo , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Infarto do Miocárdio/fisiopatologia , Isquemia Miocárdica/metabolismo , Neoplasias/metabolismo , Renina/metabolismo
3.
Front Endocrinol (Lausanne) ; 12: 665134, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248841

RESUMO

Introduction: Neuropilin-1(NRP1) is a cofactor that enhances SARS-CoV-2 coronavirus cell infectivity when co-expressed with angiotensin-converting enzyme 2(ACE2). The Renin-Angiotensin System (RAS) is activated in type 2 diabetes (T2D); therefore, the aim of this study was to determine if hypoglycaemia-induced stress in T2D would potentiate serum NRP1(sNRP1) levels, reflecting an increased risk for SARS-CoV-2 infection. Methods: A case-control study of aged-matched T2D (n = 23) and control (n = 23) subjects who underwent a hyperinsulinemic clamp over 1-hour to hypoglycemia(<40mg/dl) with subsequent timecourse of 4-hours and 24-hours. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement determined RAS-related proteins: renin (REN), angiotensinogen (AGT), ACE2, soluble NRP1(sNRP1), NRP1 ligands (Vascular endothelial growth factor, VEGF and Class 3 Semaphorins, SEM3A) and NRP1 proteolytic enzyme (A Disintegrin and Metalloproteinase 9, ADAM9). Results: Baseline RAS overactivity was present with REN elevated and AGT decreased in T2D (p<0.05); ACE2 was unchanged. Baseline sNRP1, VEGF and ADAM9 did not differ between T2D and controls and remained unchanged in response to hypoglycaemia. However, 4-hours post-hypoglycemia, sNRP1, VEGF and ADAM9 were elevated in T2D(p<0.05). SEMA3A was not different at baseline; at hypoglycemia, SEMA3A decreased in controls only. Post-hypoglycemia, SEMA3A levels were higher in T2D versus controls. sNRP1 did not correlate with ACE2, REN or AGT. T2D subjects stratified according to ACE inhibitor (ACEi) therapies showed no difference in sNRP1 levels at either glucose normalization or hypoglycaemia. Conclusion: Hypoglycemia potentiated both plasma sNRP1 level elevation and its ligands VEGF and SEMA3A, likely through an ADAM9-mediated mechanism that was not associated with RAS overactivity or ACEi therapy; however, whether this is protective or promotes increased risk for SARS-CoV-2 infection in T2D is unclear. Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT03102801.


Assuntos
Proteínas ADAM/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemia/metabolismo , Proteínas de Membrana/metabolismo , Neuropilina-1/metabolismo , Semaforina-3A/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Idoso , Angiotensinas/metabolismo , COVID-19 , Feminino , Técnica Clamp de Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Proteção , Renina/metabolismo , Fatores de Risco , SARS-CoV-2
4.
Nat Commun ; 12(1): 3683, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140503

RESUMO

Blood pressure has a daily pattern, with higher values in the active period. Its elevation at the onset of the active period substantially increases the risk of fatal cardiovascular events. Renin secretion stimulated by renal sympathetic neurons is considered essential to this process; however, its regulatory mechanism remains largely unknown. Here, we show the importance of transient receptor potential melastatin-related 6 (TRPM6), a Mg2+-permeable cation channel, in augmenting renin secretion in the active period. TRPM6 expression is significantly reduced in the distal convoluted tubule of hypotensive Cnnm2-deficient mice. We generate kidney-specific Trpm6-deficient mice and observe a decrease in blood pressure and a disappearance of its circadian variation. Consistently, renin secretion is not augmented in the active period. Furthermore, renin secretion after pharmacological activation of ß-adrenoreceptor, the target of neuronal stimulation, is abrogated, and the receptor expression is decreased in renin-secreting cells. These results indicate crucial roles of TRPM6 in the circadian regulation of blood pressure.


Assuntos
Pressão Sanguínea/fisiologia , Túbulos Renais Distais/metabolismo , Rim/metabolismo , Renina/metabolismo , Canais de Cátion TRPM/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , Pressão Sanguínea/genética , Proteínas de Transporte de Cátions/deficiência , Proteínas de Transporte de Cátions/genética , Linhagem Celular , Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Regulação para Baixo , Feminino , Regulação da Expressão Gênica/genética , Homeostase , Isoproterenol/farmacologia , Rim/patologia , Magnésio/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , Interferência de RNA , Canais de Cátion TRPM/deficiência , Canais de Cátion TRPM/genética , Regulação para Cima
5.
Nat Rev Nephrol ; 17(7): 481-492, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33824491

RESUMO

The intrarenal renin-angiotensin system is critical for the regulation of tubule sodium reabsorption, renal haemodynamics and blood pressure. The excretion of renin in urine can result from its increased filtration, the inhibition of renin reabsorption by megalin in the proximal tubule, or its secretion by the principal cells of the collecting duct. Modest increases in circulating or intrarenal angiotensin II (ANGII) stimulate the synthesis and secretion of angiotensinogen in the proximal tubule, which provides sufficient substrate for collecting duct-derived renin to form angiotensin I (ANGI). In models of ANGII-dependent hypertension, ANGII suppresses plasma renin, suggesting that urinary renin is not likely to be the result of increased filtered load. In the collecting duct, ANGII stimulates the synthesis and secretion of prorenin and renin through the activation of ANGII type 1 receptor (AT1R) expressed primarily by principal cells. The stimulation of collecting duct-derived renin is enhanced by paracrine factors including vasopressin, prostaglandin E2 and bradykinin. Furthermore, binding of prorenin and renin to the prorenin receptor in the collecting duct evokes a number of responses, including the non-proteolytic enzymatic activation of prorenin to produce ANGI from proximal tubule-derived angiotensinogen, which is then converted into ANGII by luminal angiotensin-converting enzyme; stimulation of the epithelial sodium channel (ENaC) in principal cells; and activation of intracellular pathways linked to the upregulation of cyclooxygenase 2 and profibrotic genes. These findings suggest that dysregulation of the renin-angiotensin system in the collecting duct contributes to the development of hypertension by enhancing sodium reabsorption and the progression of kidney injury.


Assuntos
Hipertensão/fisiopatologia , Túbulos Renais Coletores/fisiopatologia , Sistema Renina-Angiotensina/fisiologia , Angiotensina II/metabolismo , Humanos , Receptores de Superfície Celular/fisiologia , Renina/metabolismo
7.
Biomolecules ; 11(4)2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33916968

RESUMO

This study investigated the expression of components of the renin-angiotensin system (RAS) by cancer stem cells (CSCs) we have recently demonstrated in renal clear cell carcinoma (RCCC). Fifteen RCCC tissue samples underwent immunohistochemical staining for components of the RAS: renin, pro-renin receptor (PRR), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), and angiotensin II receptor 2 (AT2R). Immunofluorescence co-staining or double immunohistochemical staining of these components of the RAS with stemness-associated markers OCT4 or KLF4 was performed on two of the samples. Protein and transcript expression of these components of the RAS in six RCCC tissue samples was investigated using western blotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR), respectively. In addition, angiotensin II receptor 1 (AT1R) was investigated using RT-qPCR only. Immunohistochemical staining demonstrated expression of renin, PRR, and ACE2 in 11, 13, and 13 out of 15 RCCC samples, respectively, while AT2R was expressed in all 15 samples. ACE was detected in the endothelium of normal vasculature only. Double immunohistochemical staining demonstrated localization of ACE2, but not renin, to the KLF4+ CSCs. Immunofluorescence staining showed localization of PRR and AT2R to the OCT4+ CSCs. Western blotting confirmed protein expression of all components of the RAS except renin. RT-qPCR demonstrated transcript expression of all components of the RAS including AT1R, but not AT2R, in all six RCCC tissue samples. This study demonstrated expression of PRR, ACE2, and AT2R by the CSCs within RCCC. Further studies may lead to novel therapeutic targeting of CSCs by manipulation of the RAS in the treatment of this aggressive cancer.


Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Células-Tronco Neoplásicas/metabolismo , Sistema Renina-Angiotensina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/metabolismo , Feminino , Humanos , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/citologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Renina/genética , Renina/metabolismo
8.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33669059

RESUMO

The renin-angiotensin-aldosterone system (RAAS) is implicated in hypertension and kidney disease. The developing kidney can be programmed by various early-life insults by so-called renal programming, resulting in hypertension and kidney disease in adulthood. This theory is known as developmental origins of health and disease (DOHaD). Conversely, early RAAS-based interventions could reverse program processes to prevent a disease from occurring by so-called reprogramming. In the current review, we mainly summarize (1) the current knowledge on the RAAS implicated in renal programming; (2) current evidence supporting the connections between the aberrant RAAS and other mechanisms behind renal programming, such as oxidative stress, nitric oxide deficiency, epigenetic regulation, and gut microbiota dysbiosis; and (3) an overview of how RAAS-based reprogramming interventions may prevent hypertension and kidney disease of developmental origins. To accelerate the transition of RAAS-based interventions for prevention of hypertension and kidney disease, an extended comprehension of the RAAS implicated in renal programming is needed, as well as a greater focus on further clinical translation.


Assuntos
Hipertensão/metabolismo , Nefropatias/metabolismo , Rim/crescimento & desenvolvimento , Néfrons/crescimento & desenvolvimento , Sistema Renina-Angiotensina , Renina/metabolismo , Adulto , Animais , Modelos Animais de Doenças , Disbiose/metabolismo , Epigênese Genética , Humanos , Hipertensão/genética , Rim/metabolismo , Nefropatias/enzimologia , Nefropatias/genética , Néfrons/citologia , Néfrons/metabolismo , Óxido Nítrico/deficiência , Óxido Nítrico/metabolismo , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia
9.
Int J Mol Sci ; 22(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525532

RESUMO

Numerous evidence corroborates roles of gap junctions/hemichannels in proper kidney development. We analyzed how Dab1 gene functional silencing influences expression and localization of Cx37, Cx40, Cx43, Cx45, Panx1 and renin in postnatal kidneys of yotari mice, by using immunohistochemistry and electron microscopy. Dab1 Δ102/221 might lead to the activation of c-Src tyrosine kinase, causing the upregulation of Cx43 in the medulla of yotari mice. The expression of renin was more prominent in yotari mice (p < 0.001). Renin granules were unusually present inside the vascular walls of glomeruli capillaries, in proximal and distal convoluted tubules and in the medulla. Disfunction of Cx40 is likely responsible for increased atypically positioned renin cells which release renin in an uncontrolled fashion, but this doesn't rule out simultaneous involvement of other Cxs, such as Cx45 which was significantly increased in the yotari cortex. The decreased Cx37 expression in yotari medulla might contribute to hypertension reduction provoked by high renin expression. These findings imply the relevance of Cxs/Panx1 as markers of impaired kidney function (high renin) in yotari mice and that they have a role in the preservation of intercellular signaling and implicate connexopathies as the cause of premature death of yotari mice.


Assuntos
Conexina 43/genética , Conexinas/genética , Glomérulos Renais/metabolismo , Proteínas do Tecido Nervoso/genética , Renina/genética , Animais , Animais Recém-Nascidos , Conexina 43/metabolismo , Conexinas/metabolismo , Junções Comunicantes/metabolismo , Junções Comunicantes/patologia , Regulação da Expressão Gênica no Desenvolvimento , Glomérulos Renais/crescimento & desenvolvimento , Glomérulos Renais/patologia , Medula Renal/crescimento & desenvolvimento , Medula Renal/metabolismo , Medula Renal/patologia , Túbulos Renais/crescimento & desenvolvimento , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/metabolismo , Renina/metabolismo , Transdução de Sinais
10.
Methods Mol Biol ; 2235: 169-180, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33576977

RESUMO

Renal pericytes have a critical importance for angiogenesis and vascular remodeling, medullary blood flow regulation, and development of fibrosis. An emerging role for kidney pericytes is their ability to induce renin expression and synthesis. Here, we present methods for purification of human renal pericytes, their primary culture, and differentiation into renin-producing cells. Possible applications of these protocols include investigations into (1) renin cell recruitment mechanisms, (2) modulation of renin expression/secretion by small molecules, and (3) renin expression/secretion in nonrenal pericytes. A potential therapeutic application of this work is the identification of new players regulating the renin-angiotensin system.


Assuntos
Pericitos/metabolismo , Cultura Primária de Células/métodos , Sistema Renina-Angiotensina/fisiologia , Angiotensinas/metabolismo , Animais , Técnicas de Cultura de Células/métodos , Diferenciação Celular/fisiologia , Humanos , Rim/metabolismo , Renina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos
11.
Nephrol Dial Transplant ; 36(5): 793-803, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33416889

RESUMO

BACKGROUND: In chronic kidney disease, the activation of the renin-angiotensin-aldosterone system (RAAS) and renal inflammation stimulates renal fibrosis and the progression to end-stage renal disease. The low levels of vitamin D receptor (VDR) and its activators (VDRAs) contribute to worsen secondary hyperparathyroidism and renal fibrosis. METHODS: The 7/8 nephrectomy model of experimental chronic renal failure (CRF) was used to examine the anti-fibrotic effects of treatment with two VDRAs, paricalcitol and calcitriol, at equivalent doses (3/1 dose ratio) during 4 weeks. RESULTS: CRF increased the activation of the RAAS, renal inflammation and interstitial fibrosis. Paricalcitol treatment reduced renal collagen I and renal interstitial fibrosis by decreasing the activation of the RAAS through renal changes in renin, angiotensin receptor 1 (ATR1) and ATR2 mRNAs levels and renal inflammation by decreasing renal inflammatory leucocytes (CD45), a desintegrin and metaloproteinase mRNA, transforming growth factor beta mRNA and protein, and maintaining E-cadherin mRNA levels. Calcitriol showed similar trends without significant changes in most of these biomarkers. CONCLUSIONS: Paricalcitol effectively attenuated the renal interstitial fibrosis induced by CRF through a combination of inhibitory actions on the RAAS, inflammation and epithelial/mesenchymal transition.


Assuntos
Calcitriol , Animais , Biomarcadores/metabolismo , Calcitriol/farmacologia , Ergocalciferóis , Fibrose , Hiperparatireoidismo Secundário/tratamento farmacológico , Inflamação/metabolismo , Rim/metabolismo , Falência Renal Crônica/complicações , Receptores de Calcitriol/metabolismo , Insuficiência Renal Crônica/complicações , Renina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos
12.
Cells ; 10(2)2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33513805

RESUMO

We investigated the expression of components of the renin-angiotensin system (RAS) by cancer stem cell (CSC) subpopulations in metastatic head and neck cutaneous squamous cell carcinoma (mHNcSCC). Immunohistochemical staining demonstrated expression of prorenin receptor (PRR), angiotensin-converting enzyme (ACE), and angiotensin II receptor 2 (AT2R) in all cases and angiotensinogen in 14 cases; however, renin and ACE2 were not detected in any of the 20 mHNcSCC tissue samples. Western blotting showed protein expression of angiotensinogen in all six mHNcSCC tissue samples, but in none of the four mHNcSCC-derived primary cell lines, while PRR was detected in the four cell lines only. RT-qPCR confirmed transcripts of angiotensinogen, PRR, ACE, and angiotensin II receptor 1 (AT1R), but not renin or AT2R in all four mHNcSCC tissue samples and all four mHNcSCC-derived primary cell lines, while ACE2 was expressed in the tissue samples only. Double immunohistochemical staining on two of the mHNcSCC tissue samples showed expression of angiotensinogen by the SOX2+ CSCs within the tumor nests (TNs), and immunofluorescence showed expression of PRR and AT2R by the SOX2+ CSCs within the TNs and the peritumoral stroma (PTS). ACE was expressed on the endothelium of the tumor microvessels within the PTS. We demonstrated expression of angiotensinogen by CSCs within the TNs, PRR, and AT2R by the CSCs within the TNs and the PTS, in addition to ACE on the endothelium of tumor microvessels in mHNcSCC.


Assuntos
Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Sistema Renina-Angiotensina , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Idoso , Idoso de 80 Anos ou mais , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/irrigação sanguínea , Neoplasias de Cabeça e Pescoço/genética , Humanos , Microvasos/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Renina/genética , Renina/metabolismo , Sistema Renina-Angiotensina/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/irrigação sanguínea , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Células Estromais/metabolismo , Células Estromais/patologia
13.
Artigo em Inglês | MEDLINE | ID: mdl-33461701

RESUMO

Betaxolol is a relatively cardioselective ß-adrenoceptor blocking drug, with no partial agonist (intrinsic sympathomimetic) activity and weak membrane-stabilizing (local anesthetic) activity. Betaxolol selectively and competitively binds to and blocks beta-1 (ß1) adrenergic receptors in the heart, thereby decreasing cardiac contractility and rate. This leads to a reduction in cardiac output and lowers blood pressure. When applied topically in the eye, this agent reduces aqueous humor secretion and lowers the intraocular pressure (IOP). In addition, betaxolol prevents the release of renin, a hormone secreted by the kidneys that causes constriction of blood vessels. Betaxolol (S)-(-)-enantiomer shows higher pharmacological activity. This chapter provides a complete review of nomenclature, physiochemical properties, methods of preparation, identification techniques and various qualitative and quantitative analytical techniques as well as pharmacology of betaxolol. In addition, the chapter also includes review of several methods for enantiomeric separation betaxolol using chromatographic techniques.


Assuntos
Antagonistas Adrenérgicos beta , Betaxolol , Oftalmopatias/tratamento farmacológico , Antagonistas Adrenérgicos beta/farmacologia , Betaxolol/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Coração/efeitos dos fármacos , Humanos , Pressão Intraocular/efeitos dos fármacos , Rim/efeitos dos fármacos , Renina/metabolismo
14.
Kidney Int ; 99(1): 134-147, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32918942

RESUMO

Renin production by the kidney is of vital importance for salt, volume, and blood pressure homeostasis. The lack of human models hampers investigation into the regulation of renin and its relevance for kidney physiology. To develop such a model, we used human induced pluripotent stem cell-derived kidney organoids to study the role of renin and the renin-angiotensin system in the kidney. Extensive characterization of the kidney organoids revealed kidney-specific cell populations consisting of podocytes, proximal and distal tubular cells, stromal cells and endothelial cells. We examined the presence of various components of the renin-angiotensin system such as angiotensin II receptors, angiotensinogen, and angiotensin-converting enzymes 1 and 2. We identified by single-cell sequencing, immunohistochemistry, and functional assays that cyclic AMP stimulation induces a subset of pericytes to increase the synthesis and secretion of enzymatically active renin. Renin production by the organoids was responsive to regulation by parathyroid hormone. Subcutaneously implanted kidney organoids in immunodeficient IL2Ry-/-Rag2-/- mice were successfully vascularized, maintained tubular and glomerular structures, and retained capacity to produce renin two months after implantation. Thus, our results demonstrate that kidney organoids express renin and provide insights into the endocrine potential of human kidney organoids, which is important for regenerative medicine in the context of the endocrine system.


Assuntos
Células-Tronco Pluripotentes Induzidas , Renina , Angiotensina II/metabolismo , Angiotensinogênio/metabolismo , Animais , Células Endoteliais/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Rim/metabolismo , Camundongos , Organoides/metabolismo , Renina/metabolismo , Sistema Renina-Angiotensina
15.
Peptides ; 135: 170428, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33065209

RESUMO

In November 2019 the first cases of a novel acute respiratory syndrome has been reported in Wuhan province, China. Soon after, in January 2020 the World Health Organization declared a pandemic state due to the dissemination of a virus named SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the cause of coronavirus disease 2019 (COVID-19). Being an unknown disease, it is essential to assess not only its main characteristic features and overall clinical symptomatology but also its patient infection mode and propagation to design appropriate clinical interventions and treatments. In this review the pathophysiology of SARS-CoV-2 infection and how the virus enters the cells and activates the immune system are described. The role of three systems involved in the SARS- CoV-2 infection (renin-angiotensin, kinin and coagulation systems) is discussed with the objectives to identify and try to explain several of the events observed during the evolution of the disease and to suggest possible targets for therapeutic interventions.


Assuntos
COVID-19/fisiopatologia , Calicreínas/metabolismo , Cininas/metabolismo , Sistema Renina-Angiotensina/fisiologia , SARS-CoV-2/patogenicidade , Animais , Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/transmissão , Reposicionamento de Medicamentos , Interações Hospedeiro-Patógeno , Humanos , Renina/metabolismo , SARS-CoV-2/genética , Internalização do Vírus
16.
Mol Cell Endocrinol ; 522: 111118, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33340569

RESUMO

Pregnancy demands major cardiovascular, renal and endocrine changes to provide an adequate blood supply for the growing fetus. The renin-angiotensin-aldosterone system plays a key role in this adaptation process. One of its components, prorenin, is released in significant amounts from the ovary and uteroplacental unit. This review describes the sources of prorenin in the periconception period and in pregnancy, including its modulation by in-vitro fertilization protocols, and discusses its potential effects, among others focusing on preeclampsia. It ends with discussing the long-term consequences, even in later life, of inappropriate renin-angiotensin-aldosterone system activity in pregnancy and offers directions for future research. Ultimately, a full understanding of the role of prorenin periconceptionally and during pregnancy will help to develop tools to diagnose and/or prevent reproductive complications.


Assuntos
Renina/metabolismo , Animais , Feminino , Hemodinâmica , Humanos , Modelos Biológicos , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/metabolismo , Gravidez , Biossíntese de Proteínas , Renina/biossíntese , Sistema Renina-Angiotensina
17.
Biomed Pharmacother ; 133: 110824, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378988

RESUMO

BACKGROUND: LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNi), is reported to play a cardioprotective role after acute myocardial infarction (AMI). Angiotensin-converting enzyme inhibitors(ACEIs) have similar roles. However, it is unclear whether the combination of the two drugs has a better protective effect. The purpose of this study was to investigate the effect of this combination therapy after AMI. METHODS: Male C57BL/6 J mice subjected to ligation of left anterior descending artery were treated for 4 weeks with LCZ696, ACEI(benazepril), or both(combination therapy) after induction of MI. Cardiac function, hemodynamics, and inflammatory factors were evaluated at 1 st day, 14th day, and 28th day. Heart weight and myocardial fibrosis were measured at the end of the experiment. RESULTS: Blood pressure was lower in all treatment groups than in the control group. The combination therapy group had the strongest antihypertensive effect. Compared with LCZ696 or benazepril, treatment with combination therapy increased ejection fraction, fractional shortening, and cardiac output and decreased N-terminal pro-B-type natriuretic peptide(NT-proBNP). The ratios of heart weight to body weight in all treatment groups were less than that in the control group. Compared with the control and LCZ696 group, the fibrotic area in the combination therapy group was suppressed and had a lower level of TGF-ß1 in the left ventricle. The plasma concentration of bradykinin and renin in the combination therapy group were highest among groups at 14th and 28th day. CONCLUSIONS: LCZ696 in combination with benazepril showed better positive effects in modulating heart failure and myocardial fibrosis after acute AMI in mice and affect some inflammatory markers.


Assuntos
Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Benzazepinas/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/complicações , Miocárdio/patologia , Inibidores de Proteases/farmacologia , Tetrazóis/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Combinação de Medicamentos , Quimioterapia Combinada , Fibrose , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Neprilisina/antagonistas & inibidores , Renina/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
18.
Bioessays ; 43(3): e2000112, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33336824

RESUMO

This renin-angiotensin system (RAS) interpretation is focused on differences in tissue dependence on RAS and on the topological hierarchy that allows mediators to act only on downstream tissues. Dependence of tissues on RAS: Tested by expectation maximization clustering of the RNA human tissue expression (https://biogps.org/). ACE and vasoconstrictive AT1R clustered with the prorenin receptor. ACE2 and dilatory MAS1 clustered with nine RAS-related genes, highly expressed in: Liver; Cardiac_Myocytes; Skeletal_Muscle; Uterus; Kidney; Lung; Small_Intestine; Smooth_Muscle. RAS and stress accumulation: While prorenin is active after binding to its receptor, binding of soluble renin increases its enzymatic activity several times. Increased renin secretion multiplies the overall capacity for producing Ang I, leading to hypertension and increased vascular resistance. Coronavirus infection and comorbidities: Cardiorespiratory failure during infection is linked to the previously altered RAS role in lungs and myocardium. Reduced vasodilation by ACE2 lead to vasoconstriction and suboptimal tissue perfusion patterns. Also see the video abstract here https://www.youtube.com/watch?v=Jf0Iped-Mws.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , COVID-19/genética , Hipertensão/genética , Sistema Renina-Angiotensina/genética , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Idoso , Angiotensina I/genética , Angiotensina I/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , COVID-19/mortalidade , COVID-19/virologia , Regulação da Expressão Gênica , Humanos , Hipertensão/metabolismo , Hipertensão/mortalidade , Hipertensão/virologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Miocárdio/metabolismo , Miocárdio/patologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Renina/genética , Renina/metabolismo , Transdução de Sinais , Análise de Sobrevida
19.
Sci Rep ; 10(1): 21154, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33273645

RESUMO

Obesity has been firmly established as a major risk factor for common disease states including hypertension, type 2 diabetes mellitus, and chronic kidney disease. Increased body mass index (BMI) contributes to the activation of both the systemic and intra-tubular renin angiotensin systems (RAS), which are in turn associated with increased blood pressure (BP) and kidney damage. In this cross-sectional study, 43 subjects of normal or increased body weight were examined in order to determine the correlation of BMI or body fat mass (BFM) with blood pressure, fasting blood glucose (FBG), and urinary kidney injury markers such as interleukin-18 (IL-18), connective tissue growth factor (CTGF), neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 (KIM-1). Our results showed that: (1) subjects with increased body weight showed significantly higher BP, BFM, total body water and metabolic age; (2) BMI was positively correlated to both systolic (R2 = 0.1384, P = 0.01) and diastolic BP (R2 = 0.2437, P = 0.0008); (3) BFM was positively correlated to DBP (R2 = 0.1232, P = 0.02) and partially correlated to urine protein (R2 = 0.047, P = 0.12) and FBG (R2 = 0.07, P = 0.06); (4) overweight young adults had higher urinary mRNA levels of renin, angiotensinogen, IL-18 and CTGF. These suggest that BMI directly affects BP, kidney injury markers, and the activation of the intra-tubular RAS even in normotensive young adults. Given that BMI measurements and urine analyses are non-invasive, our findings may pave the way to developing a new and simple method of screening for the risk of chronic kidney disease in adults.


Assuntos
Biomarcadores/urina , Rim/lesões , Rim/metabolismo , Sobrepeso/genética , Sobrepeso/urina , Sistema Renina-Angiotensina/genética , Tecido Adiposo , Adiposidade , Adolescente , Angiotensinogênio/metabolismo , Glicemia/metabolismo , Pressão Sanguínea , Índice de Massa Corporal , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/urina , Jejum/sangue , Feminino , Humanos , Interleucina-18/genética , Interleucina-18/urina , Rim/fisiopatologia , Modelos Lineares , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Renina/metabolismo , Adulto Jovem
20.
J Vis Exp ; (164)2020 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-33165324

RESUMO

Renal artery stenosis is a common condition in patients with coronary or peripheral vascular disease where the renin angiotensin aldosterone system (RAAS) is overactivated. In this context, there is a narrowing of the renal arteries that stimulate an increase in the expression and release of renin, the rate-limiting protease in RAAS. The resulting rise in renin expression is a known driver of renovascular hypertension, frequently associated with kidney injury and end organ damage. Thus, there is a great interest in developing novel treatments for this condition. The molecular and cellular mechanism of renin control in renal artery stenosis is not fully understood and warrants further investigation. To induce renal artery stenosis in mice, a modified 2 kidney 1 clip (2K1C) Goldblatt mouse model was developed. The right kidney was stenosed in wild type mice and sham operated mice were used as control. After renal artery stenosis, we determined renin expression and kidney injury. Kidneys were harvested, and fresh cortices were used to determine protein and mRNA expression of renin. This animal model is reproducible and can be used to study pathophysiological responses, molecular and cellular pathways involved in renovascular hypertension and kidney injury.


Assuntos
Injúria Renal Aguda/diagnóstico , Modelos Animais de Doenças , Rim/cirurgia , Lipocalina-2/metabolismo , Obstrução da Artéria Renal/fisiopatologia , Artéria Renal/fisiopatologia , Renina/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Animais , Pressão Sanguínea , Feminino , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obstrução da Artéria Renal/complicações , Obstrução da Artéria Renal/metabolismo
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