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1.
J Physiol ; 602(8): 1605-1621, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37128952

RESUMO

Cardiac arrhythmias pose a major threat to a patient's health, yet prove to be often difficult to predict, prevent and treat. A key mechanism in the occurrence of arrhythmias is disturbed Ca2+ homeostasis in cardiac muscle cells. As a Ca2+-activated non-selective cation channel, TRPM4 has been linked to Ca2+-induced arrhythmias, potentially contributing to translating an increase in intracellular Ca2+ concentration into membrane depolarisation and an increase in cellular excitability. Indeed, evidence from genetically modified mice, analysis of mutations in human patients and the identification of a TRPM4 blocking compound that can be applied in vivo further underscore this hypothesis. Here, we provide an overview of these data in the context of our current understanding of Ca2+-dependent arrhythmias.

2.
Nature ; 555(7698): 662-666, 2018 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-29539642

RESUMO

Acute pain represents a crucial alarm signal to protect us from injury. Whereas the nociceptive neurons that convey pain signals were described more than a century ago, the molecular sensors that detect noxious thermal or mechanical insults have yet to be fully identified. Here we show that acute noxious heat sensing in mice depends on a triad of transient receptor potential (TRP) ion channels: TRPM3, TRPV1, and TRPA1. We found that robust somatosensory heat responsiveness at the cellular and behavioural levels is observed only if at least one of these TRP channels is functional. However, combined genetic or pharmacological elimination of all three channels largely and selectively prevents heat responses in both isolated sensory neurons and rapidly firing C and Aδ sensory nerve fibres that innervate the skin. Strikingly, Trpv1-/-Trpm3-/-Trpa1-/- triple knockout (TKO) mice lack the acute withdrawal response to noxious heat that is necessary to avoid burn injury, while showing normal nociceptive responses to cold or mechanical stimuli and a preserved preference for moderate temperatures. These findings indicate that the initiation of the acute heat-evoked pain response in sensory nerve endings relies on three functionally redundant TRP channels, representing a fault-tolerant mechanism to avoid burn injury.


Assuntos
Temperatura Alta/efeitos adversos , Dor Nociceptiva/fisiopatologia , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPM/metabolismo , Canais de Cátion TRPV/metabolismo , Sensação Térmica/fisiologia , Animais , Queimaduras/fisiopatologia , Queimaduras/prevenção & controle , Temperatura Baixa/efeitos adversos , Feminino , Masculino , Camundongos , Camundongos Knockout , Terminações Nervosas/fisiologia , Fibras Nervosas/fisiologia , Nociceptividade/fisiologia , Células Receptoras Sensoriais/fisiologia , Pele/inervação , Pele/fisiopatologia , Canal de Cátion TRPA1/deficiência , Canal de Cátion TRPA1/genética , Canais de Cátion TRPM/deficiência , Canais de Cátion TRPM/genética , Canais de Cátion TRPV/deficiência , Canais de Cátion TRPV/genética , Sensação Térmica/genética
3.
Nature ; 559(7713): E7, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29720653

RESUMO

In this Letter, the trace is missing in Fig. 1e. This error has been corrected online.

4.
BMC Biol ; 21(1): 96, 2023 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-37101159

RESUMO

BACKGROUND: Mossy cells comprise a large fraction of excitatory neurons in the hippocampal dentate gyrus, and their loss is one of the major hallmarks of temporal lobe epilepsy (TLE). The vulnerability of mossy cells in TLE is well known in animal models as well as in patients; however, the mechanisms leading to cellular death is unclear. RESULTS: Transient receptor potential melastatin 4 (TRPM4) is a Ca2+-activated non-selective cation channel regulating diverse physiological functions of excitable cells. Here, we identified that TRPM4 is present in hilar mossy cells and regulates their intrinsic electrophysiological properties including spontaneous activity and action potential dynamics. Furthermore, we showed that TRPM4 contributes to mossy cells death following status epilepticus and therefore modulates seizure susceptibility and epilepsy-related memory deficits. CONCLUSIONS: Our results provide evidence for the role of TRPM4 in MC excitability both in physiological and pathological conditions.


Assuntos
Epilepsia do Lobo Temporal , Animais , Potenciais de Ação , Epilepsia do Lobo Temporal/metabolismo , Epilepsia do Lobo Temporal/patologia , Fibras Musgosas Hipocampais/metabolismo , Fibras Musgosas Hipocampais/patologia , Canais de Cátion TRPM/metabolismo
5.
Pediatr Nephrol ; 38(9): 3043-3053, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-36939917

RESUMO

BACKGROUND: Young autosomal dominant polycystic kidney disease (ADPKD) patients are becoming the new target population for the development of new treatment options. Determination of a reliable equation for estimated glomerular filtration rate (eGFR) from early stages is needed with the promising potential interventional therapies. METHODS: Prospective and longitudinal study on a cohort of 68 genotyped ADPKD patients (age range 0-23 years) with long-term follow-up. Commonly used equations for eGFR were compared for their relative performance. RESULTS: The revised Schwartz formula (CKiD) showed a highly significant decline in eGFR with aging (- 3.31 mL/min/1.73 m2/year, P < 0.0001). The recently updated equation by the Schwartz group (CKiDU25) showed a smaller (- 0.90 mL/min/1.73 m2/year) but significant (P = 0.001) decline in eGFR with aging and also showed a significant sex difference (P < 0.0001), not observed by the other equations. In contrast, the full age spectrum (FAS) equations (FAS-SCr, FAS-CysC, and the combined) showed no age and sex dependency. The prevalence of hyperfiltration is highly dependent on the formula used, and the highest prevalence was observed with the CKiD Equation (35%). CONCLUSIONS: The most widely used methods to calculate eGFR in ADPKD children (CKiD and CKiDU25 equations) were associated with unexpected age or sex differences. The FAS equations were age- and sex-independent in our cohort. Hence, the switch from the CKiD to CKD-EPI equation at the transition from pediatric to adult care causes implausible jumps in eGFR, which could be misinterpreted. Having reliable methods to calculate eGFR is indispensable for clinical follow-up and clinical trials. A higher resolution version of the Graphical abstract is available as Supplementary information.


Assuntos
Rim Policístico Autossômico Dominante , Insuficiência Renal Crônica , Transição para Assistência do Adulto , Humanos , Criança , Feminino , Masculino , Adulto Jovem , Recém-Nascido , Lactente , Pré-Escolar , Adolescente , Adulto , Taxa de Filtração Glomerular , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/genética , Estudos Longitudinais , Estudos Prospectivos , Creatinina
6.
Eur Heart J ; 43(40): 4195-4207, 2022 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-35822895

RESUMO

AIMS: Cardiac arrhythmias are a major factor in the occurrence of morbidity and sudden death in patients with cardiovascular disease. Disturbances of Ca2+ homeostasis in the heart contribute to the initiation and maintenance of cardiac arrhythmias. Extrasystolic increases in intracellular Ca2+ lead to delayed afterdepolarizations and triggered activity, which can result in heart rhythm abnormalities. It is being suggested that the Ca2+-activated nonselective cation channel TRPM4 is involved in the aetiology of triggered activity, but the exact contribution and in vivo significance are still unclear. METHODS AND RESULTS: In vitro electrophysiological and calcium imaging technique as well as in vivo intracardiac and telemetric electrocardiogram measurements in physiological and pathophysiological conditions were performed. In two distinct Ca2+-dependent proarrhythmic models, freely moving Trpm4-/- mice displayed a reduced burden of cardiac arrhythmias. Looking further into the specific contribution of TRPM4 to the cellular mechanism of arrhythmias, TRPM4 was found to contribute to a long-lasting Ca2+ overload-induced background current, thereby regulating cell excitability in Ca2+ overload conditions. To expand these results, a compound screening revealed meclofenamate as a potent antagonist of TRPM4. In line with the findings from Trpm4-/- mice, 10 µM meclofenamate inhibited the Ca2+ overload-induced background current in ventricular cardiomyocytes and 15 mg/kg meclofenamate suppressed catecholaminergic polymorphic ventricular tachycardia-associated arrhythmias in a TRPM4-dependent manner. CONCLUSION: The presented data establish that TRPM4 represents a novel target in the prevention and treatment of Ca2+-dependent triggered arrhythmias.


Assuntos
Canais de Cátion TRPM , Taquicardia Ventricular , Camundongos , Animais , Cálcio/metabolismo , Ácido Meclofenâmico/metabolismo , Arritmias Cardíacas , Miócitos Cardíacos/metabolismo , Canais de Cátion TRPM/metabolismo
7.
J Biol Chem ; 297(3): 101015, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34329682

RESUMO

Transient receptor potential cation channel subfamily M member 4 (TRPM4) is a Ca2+-activated nonselective cation channel that mediates membrane depolarization. Although, a current with the hallmarks of a TRPM4-mediated current has been previously reported in pancreatic acinar cells (PACs), the role of TRPM4 in the regulation of acinar cell function has not yet been explored. In the present study, we identify this TRPM4 current and describe its role in context of Ca2+ signaling of PACs using pharmacological tools and TRPM4-deficient mice. We found a significant Ca2+-activated cation current in PACs that was sensitive to the TRPM4 inhibitors 9-phenanthrol and 4-chloro-2-[[2-(2-chlorophenoxy)acetyl]amino]benzoic acid (CBA). We demonstrated that the CBA-sensitive current was responsible for a Ca2+-dependent depolarization of PACs from a resting membrane potential of -44.4 ± 2.9 to -27.7 ± 3 mV. Furthermore, we showed that Ca2+ influx was higher in the TRPM4 KO- and CBA-treated PACs than in control cells. As hormone-induced repetitive Ca2+ transients partially rely on Ca2+ influx in PACs, the role of TRPM4 was also assessed on Ca2+ oscillations elicited by physiologically relevant concentrations of the cholecystokinin analog cerulein. These data show that the amplitude of Ca2+ signals was significantly higher in TRPM4 KO than in control PACs. Our results suggest that PACs are depolarized by TRPM4 currents to an extent that results in a significant reduction of the inward driving force for Ca2+. In conclusion, TRPM4 links intracellular Ca2+ signaling to membrane potential as a negative feedback regulator of Ca2+ entry in PACs.


Assuntos
Células Acinares/metabolismo , Sinalização do Cálcio , Potenciais da Membrana , Pâncreas Exócrino/metabolismo , Canais de Cátion TRPM/metabolismo , Animais , Cálcio/metabolismo , Feminino , Transporte de Íons , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pâncreas Exócrino/citologia , Técnicas de Patch-Clamp , Fenantrenos/farmacologia , Canais de Cátion TRPM/antagonistas & inibidores , Canais de Cátion TRPM/genética
8.
Glia ; 70(11): 2157-2168, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35809029

RESUMO

Microglia, the resident macrophages of the central nervous system, are highly motile cells that support brain development, provision neuronal signaling, and protect brain cells against damage. Proper microglial functioning requires constant cell movement and morphological changes. Interestingly, the transient receptor potential vanilloid 4 (TRPV4) channel, a calcium-permeable channel, is involved in hypoosmotic morphological changes of retinal microglia and regulates temperature-dependent movement of microglial cells both in vitro and in vivo. Despite the broad functions of TRPV4 and the recent findings stating a role for TRPV4 in microglial movement, little is known about how TRPV4 modulates cytoskeletal remodeling to promote changes of microglial motility. Here we show that acute inhibition of TRPV4, but not its constitutive absence in the Trpv4 KO cells, affects the morphology and motility of microglia in vitro. Using high-end confocal imaging techniques, we show a decrease in actin-rich filopodia and tubulin dynamics upon acute inhibition of TRPV4 in vitro. Furthermore, using acute brain slices we demonstrate that Trpv4 knockout microglia display lower ramification complexity, slower process extension speed and consequently smaller surveyed area. We conclude that TRPV4 inhibition triggers a shift in cytoskeleton remodeling of microglia influencing their migration and morphology.


Assuntos
Canais de Cátion TRPV , Canais de Potencial de Receptor Transitório , Cátions , Citoesqueleto , Microglia/fisiologia , Canais de Cátion TRPV/genética
9.
Nephrol Dial Transplant ; 37(12): 2314-2326, 2022 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-33744967

RESUMO

The apelinergic system (AS) is a novel pleiotropic system with an essential role in renal and cardiovascular physiology and disease, including water homeostasis and blood pressure regulation. It consists of two highly conserved peptide ligands, apelin and apela, and a G-protein-coupled apelin receptor. The two ligands have many isoforms and a short half-life and exert both similar and divergent effects. Vasopressin, apelin and their receptors colocalize in hypothalamic regions essential for body fluid homeostasis and interact at the central and renal levels to regulate water homeostasis and diuresis in inverse directions. In addition, the AS and renin-angiotensin system interact both systemically and in the kidney, with implications for the cardiovascular system. A role for the AS in diverse pathological states, including disorders of sodium and water balance, hypertension, heart failure, pre-eclampsia, acute kidney injury, sepsis and diabetic nephropathy, has recently been reported. Furthermore, several metabolically stable apelin analogues have been developed, with potential applications in diverse diseases. We review here what is currently known about the physiological functions of the AS, focusing on renal, cardiovascular and metabolic homeostasis, and the role of the AS in associated diseases. We also describe several hurdles and research opportunities worthy of the attention of the nephrology community.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular , Nefropatias , Receptores Acoplados a Proteínas G , Humanos , Apelina/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Rim/metabolismo , Ligantes , Receptores Acoplados a Proteínas G/metabolismo , Água/metabolismo
10.
Pediatr Nephrol ; 37(9): 1945-1955, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-34988697

RESUMO

The clinical course of autosomal dominant polycystic kidney disease (ADPKD) starts in childhood. Evidence of the beneficial impact of early nephron-protective strategies and lifestyle modifications on ADPKD prognosis is accumulating. Recent studies have described the association of overweight and obesity with rapid disease progression in adults with ADPKD. Moreover, defective glucose metabolism and metabolic reprogramming have been reported in distinct ADPKD models highlighting these pathways as potential therapeutic targets in ADPKD. Several "metabolic" approaches are currently under evaluation in adults, including ketogenic diet, food restriction, and metformin therapy. No data are available on the impact of these approaches in childhood thus far. Yet, according to World Health Organization (WHO), we are currently facing a childhood obesity crisis with an increased prevalence of overweight/obesity in the pediatric population associated with a cardio-metabolic risk profile. The present review summarizes the knowledge about the role of glucose metabolism in the pathophysiology of ADPKD and underscores the possible harm of overweight and obesity in ADPKD especially in terms of long-term cardiovascular outcomes and renal prognosis.


Assuntos
Obesidade Infantil , Rim Policístico Autossômico Dominante , Adulto , Criança , Progressão da Doença , Glucose/uso terapêutico , Humanos , Rim , Sobrepeso/complicações , Obesidade Infantil/complicações , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/terapia
11.
Pediatr Nephrol ; 36(11): 3505-3514, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33502599

RESUMO

Autosomal dominant polycystic kidney disease (ADPKD) is associated with distinct cytopenias in observational studies; the most consistent and strongest association is seen with alternations in the lymphocytic lineages. Although the underlying mechanism of these associations is unclear, it has been hypothesized to be secondary to sequestration of white blood cells in cystic organs, or related to the uremic environment in chronic kidney disease (CKD). However, since mutations in PKD1 or -2 affect several immunomodulating pathways, cytopenia may well be an unrecognized extrarenal manifestation of ADPKD. Furthermore, many important questions on the clinical implications of this finding and the effect on the disease course in these patients are unanswered. In this review article, we provide an overview of the current evidence on cytopenia in ADPKD and explore the underlying mechanisms of this association and its potential prognostic implications. Based on the current literature, we hypothesize that polycystin deficiency can disturb immune cell homeostasis and that cytopenia is thus an intrinsic feature of ADPKD, related to genetic factors. Taken together, these findings warrant further investigation to establish the exact etiology and role of cytopenia in patients with ADPKD.


Assuntos
Doenças Hematológicas , Rim Policístico Autossômico Dominante , Doenças Hematológicas/epidemiologia , Humanos , Rim Policístico Autossômico Dominante/epidemiologia , Rim Policístico Autossômico Dominante/terapia , Prognóstico
12.
Mol Cell Neurosci ; 105: 103495, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32298804

RESUMO

The vomeronasal organ (VNO), the sensory organ of the mammalian accessory olfactory system, mediates the activation of sexually dimorphic reproductive behavioral and endocrine responses in males and females. It is unclear how sexually dimorphic and state-dependent responses are generated by vomeronasal sensory neurons (VSNs). Here, we report the expression of the transient receptor potential (TRP) channel Trpm4, a Ca2+-activated monovalent cation channel, as a second TRP channel present in mouse VSNs, in addition to the diacylglycerol-sensitive Trpc2 channel. The expression of Trpm4 in the mouse VNO is sexually dimorphic and, in females, is tightly linked to their reproductive cycle. We show that Trpm4 protein expression is upregulated specifically during proestrus and estrus, when female mice are about to ovulate and become sexually active and receptive. The cyclic regulation of Trpm4 expression in female VSNs depends on ovarian sex hormones and is abolished by surgical removal of the ovaries (OVX). Trpm4 upregulation can be restored in OVX mice by systemic treatment with 17ß-estradiol, requires endogenous activity of aromatase enzyme, and is strongly reduced during late pregnancy. This cyclic regulation of Trpm4 offers a neural mechanism by which female mice could regulate the relative strength of sensory signals in their VSNs, depending on hormonal state. Trpm4 is likely to participate in sex-specific, estrous cycle-dependent and sex hormone-regulated functions of the VNO, and may serve as a previously unknown genetic substrate for dissecting mammalian sexually dimorphic cellular and behavioral responses.


Assuntos
Ovário/metabolismo , Células Receptoras Sensoriais/metabolismo , Canais de Cátion TRPM/metabolismo , Órgão Vomeronasal/metabolismo , Potenciais de Ação/fisiologia , Animais , Cálcio/metabolismo , Diglicerídeos/metabolismo , Estradiol/metabolismo , Estrogênios/metabolismo , Feminino , Masculino , Camundongos , Canais de Cátion TRPC/genética
13.
Int J Mol Sci ; 22(24)2021 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-34948309

RESUMO

Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by deficiency of polycystin-1 (PC1) or polycystin-2 (PC2). Altered autophagy has recently been implicated in ADPKD progression, but its exact regulation by PC1 and PC2 remains unclear. We therefore investigated cell death and survival during nutritional stress in mouse inner medullary collecting duct cells (mIMCDs), either wild-type (WT) or lacking PC1 (PC1KO) or PC2 (PC2KO), and human urine-derived proximal tubular epithelial cells (PTEC) from early-stage ADPKD patients with PC1 mutations versus healthy individuals. Basal autophagy was enhanced in PC1-deficient cells. Similarly, following starvation, autophagy was enhanced and cell death reduced when PC1 was reduced. Autophagy inhibition reduced cell death resistance in PC1KO mIMCDs to the WT level, implying that PC1 promotes autophagic cell survival. Although PC2 expression was increased in PC1KO mIMCDs, PC2 knockdown did not result in reduced autophagy. PC2KO mIMCDs displayed lower basal autophagy, but more autophagy and less cell death following chronic starvation. This could be reversed by overexpression of PC1 in PC2KO. Together, these findings indicate that PC1 levels are partially coupled to PC2 expression, and determine the transition from renal cell survival to death, leading to enhanced survival of ADPKD cells during nutritional stress.


Assuntos
Autofagia/fisiologia , Morte Celular/fisiologia , Inanição/metabolismo , Canais de Cátion TRPP/metabolismo , Animais , Linhagem Celular , Células Epiteliais/metabolismo , Humanos , Túbulos Renais Proximais/metabolismo , Camundongos , Rim Policístico Autossômico Dominante/metabolismo
14.
Basic Res Cardiol ; 115(6): 70, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33205255

RESUMO

Transient receptor potential melastatin 4 (TRPM4) cation channels act in cardiomyocytes as a negative modulator of the L-type Ca2+ current. Ubiquitous Trpm4 deletion in mice leads to an increased ß-adrenergic inotropy in healthy mice as well as after myocardial infarction. In this study, we set out to investigate cardiac inotropy in mice with cardiomyocyte-specific Trpm4 deletion. The results guided us to investigate the relevance of TRPM4 for catecholamine-evoked Ca2+ signaling in cardiomyocytes and inotropy in vivo in TRPM4-deficient mouse models of different genetic background. Cardiac hemodynamics were investigated using pressure-volume analysis. Surprisingly, an increased ß-adrenergic inotropy was observed in global TRPM4-deficient mice on a 129SvJ genetic background, but the inotropic response was unaltered in mice with global and cardiomyocyte-specific TRPM4 deletion on the C57Bl/6N background. We found that the expression of TRPM4 proteins is about 78 ± 10% higher in wild-type mice on the 129SvJ versus C57Bl/6N background. In accordance with contractility measurements, our analysis of the intracellular Ca2+ transients revealed an increase in ISO-evoked Ca2+ rise in Trpm4-deficient cardiomyocytes of the 129SvJ strain, but not of the C57Bl/6N strain. No significant differences were observed between the two mouse strains in the expression of other regulators of cardiomyocyte Ca2+ homeostasis. We conclude that the relevance of TRPM4 for cardiac contractility depends on homeostatic TRPM4 expression levels or the genetic endowment in different mouse strains as well as on the health/disease status. Therefore, the concept of inhibiting TRPM4 channels to improve cardiac contractility needs to be carefully explored in specific strains and species and prospectively in different genetically diverse populations of patients.


Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Miócitos Cardíacos/metabolismo , Canais de Cátion TRPM/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , Sinalização do Cálcio/efeitos dos fármacos , Isoproterenol/farmacologia , Cinética , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Contração Miocárdica , Miócitos Cardíacos/efeitos dos fármacos , Especificidade da Espécie , Canais de Cátion TRPM/deficiência , Canais de Cátion TRPM/genética , Função Ventricular Esquerda
15.
J Card Fail ; 26(7): 599-609, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32147520

RESUMO

BACKGROUND: Survival of patients with congenital heart defects including increased right ventricular pressure load (ie, tetralogy of Fallot) or pulmonary hypertension is dependent on the function of the right ventricle (RV). RV remodeling has several effects with progressive transition from compensated status to heart failure. Transient receptor potential melastatin 4 (TRPM4) forms cation channels expressed in myocardium, which was shown to modulate cardiac remodeling in the left ventricle of mice. Aim of this study was to identify the role of TRPM4 for contractile function and remodeling of the RV in a rat model of right ventricular pressure load. METHODS AND RESULTS: We performed experiments with untreated rats and under monocrotaline (MCT)-induced pressure load comparing wild-type (Trpm4+/+) and TRPM4-deficient (Trpm4-/-) rats. RV function was characterized by echocardiography and contractility measurements of isolated papillary muscles. RV hypertrophy was investigated by echocardiography and by determination of hypertrophy indices. Pulmonary arterial remodeling was evaluated by echocardiography and histology. TRPM4 protein expression in RV of human, rat and mouse was detected by Western blot and quantified in rat. TRPM4 proteins were detected in RV myocardium of rat and mouse, which were not detectable in TRPM4-deficient animals. Proteins of the same size were found in RV of a pediatric patient with tetralogy of Fallot. In untreated status, Trpm4+/+ and Trpm4-/- rats showed comparable RV contractile function and dimensions. Under pressure load (42 days after MCT injection), RV hypertrophy was significantly increased in Trpm4-/- rats compared with Trpm4+/+ controls, whereas MCT-mediated alterations in cardiac contractility and pulmonary arterial remodeling were not affected by TRPM4 inactivation in rats. Finally, TRPM4 protein expression in RV was drastically reduced in MCT-treated rats, whereas left ventricle of the same animals showed no alteration in TRPM4 expression. CONCLUSIONS: Right ventricular pressure load evoked by MCT treatment in rats leads to a prominent downregulation of TRPM4 protein expression in the RV and complete deletion of TRPM4 expression aggravates right ventricular hypertrophy. Thus, therapeutic modulation of TRPM4 expression and activity might represent a novel approach to target right ventricular remodeling in patients with pulmonary hypertension or otherwise loaded RV.


Assuntos
Insuficiência Cardíaca , Canais de Cátion TRPM , Animais , Criança , Humanos , Hipertrofia Ventricular Direita , Camundongos , Monocrotalina , Ratos , Ratos Wistar , Canais de Cátion TRPM/genética , Função Ventricular Direita , Remodelação Ventricular
16.
Neuroimage ; 188: 347-356, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30553915

RESUMO

Electrical stimulation of right Schaffer collateral in Trpm4-/- knockout and wild type rats were used to study the role of Trpm4 channels for signal processing in the hippocampal formation. Stimulation induced neuronal activity was simultaneously monitored in the CA1 region by in vivo extracellular field recordings and in the entire brain by BOLD fMRI measurements. In wild type and Trpm4-/- knockout rats, consecutive 5 Hz pulse trains elicited similar neuronal responses in the CA1 region and similar BOLD responses in the stimulated right hippocampus. Stimulus-related positive BOLD responses were also found in the left dorsal hippocampus. In contrast to the right dorsal hippocampus, baseline BOLD signals in the left hippocampus significantly decreased during consecutive stimulation trains. Similarly, slowly developing significant declines in baseline BOLD signals, in absence of any positive BOLD responses, were also observed in the right entorhinal, right piriform cortex, right basolateral amygdala and right dorsal striatum whereas baseline BOLD signals remained almost stable in the corresponding left regions. Furthermore, significant declines in baseline BOLD signals were found in the prefrontal cortex and prelimbic/infralimbic cortex. Because significant baseline BOLD declines were only observed in target regions of the right dorsal hippocampus, it might reflect functional connectivity between these regions. In all observed regions the decline in baseline BOLD signals was significantly delayed and less pronounced in Trpm4-/- knockout rats when compared to wild type rats. Thus, either Trpm4 channels are involved in mediating these baseline BOLD shifts or functional connectivity of the hippocampus is impaired in Trpm4-/- knockout rats.


Assuntos
Hipocampo/fisiologia , Canais de Cátion TRPM/fisiologia , Animais , Região CA1 Hipocampal/diagnóstico por imagem , Região CA1 Hipocampal/fisiologia , Estimulação Elétrica , Eletrocorticografia , Feminino , Lateralidade Funcional/fisiologia , Hipocampo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Ratos , Ratos Transgênicos
17.
Pediatr Nephrol ; 34(10): 1697-1715, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30215095

RESUMO

Several animal- and human-derived models are used in autosomal dominant polycystic kidney disease (ADPKD) research to gain insight in the disease mechanism. However, a consistent correlation between animal and human ADPKD models is lacking. Therefore, established human-derived models are relevant to affirm research results and translate findings into a clinical set-up. In this review, we give an extensive overview of the existing human-based cell models. We discuss their source (urine, nephrectomy and stem cell), immortalisation procedures, genetic engineering, kidney segmental origin and characterisation with nephron segment markers. We summarise the most studied pathways and lessons learned from these different ADPKD models. Finally, we issue recommendations for the derivation of human-derived cell lines and for experimental set-ups with these cell lines.


Assuntos
Rim/fisiopatologia , Rim Policístico Autossômico Dominante/fisiopatologia , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Sinalização do Cálcio , Linhagem Celular , Proliferação de Células , Cílios/patologia , Ensaios Clínicos como Assunto , Glucosidases/genética , Humanos , Rim/citologia , Rim/efeitos dos fármacos , Rim/patologia , Mutação , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/patologia , Cultura Primária de Células/métodos , Serina-Treonina Quinases TOR/metabolismo , Canais de Cátion TRPP/genética , Tolvaptan/farmacologia , Tolvaptan/uso terapêutico , Resultado do Tratamento
18.
Glia ; 66(1): 108-125, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28906027

RESUMO

Astrocyte swelling occurs after central nervous system injury and contributes to brain swelling, which can increase mortality. Mechanisms proffered to explain astrocyte swelling emphasize the importance of either aquaporin-4 (AQP4), an astrocyte water channel, or of Na+ -permeable channels, which mediate cellular osmolyte influx. However, the spatio-temporal functional interactions between AQP4 and Na+ -permeable channels that drive swelling are poorly understood. We hypothesized that astrocyte swelling after injury is linked to an interaction between AQP4 and Na+ -permeable channels that are newly upregulated. Here, using co-immunoprecipitation and Förster resonance energy transfer, we report that AQP4 physically co-assembles with the sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) monovalent cation channel to form a novel heteromultimeric water/ion channel complex. In vitro cell-swelling studies using calcein fluorescence imaging of COS-7 cells expressing various combinations of AQP4, SUR1, and TRPM4 showed that the full tripartite complex, comprised of SUR1-TRPM4-AQP4, was required for fast, high-capacity transmembrane water transport that drives cell swelling, with these findings corroborated in cultured primary astrocytes. In a murine model of brain edema involving cold-injury to the cerebellum, we found that astrocytes newly upregulate SUR1-TRPM4, that AQP4 co-associates with SUR1-TRPM4, and that genetic inactivation of the solute pore of the SUR1-TRPM4-AQP4 complex blocked in vivo astrocyte swelling measured by diolistic labeling, thereby corroborating our in vitro functional studies. Together, these findings demonstrate a novel molecular mechanism involving the SUR1-TRPM4-AQP4 complex to account for bulk water influx during astrocyte swelling. These findings have broad implications for the understanding and treatment of AQP4-mediated pathological conditions.


Assuntos
Aquaporina 4/metabolismo , Astrócitos/metabolismo , Complexos Multiproteicos/metabolismo , Receptores de Sulfonilureias/metabolismo , Canais de Cátion TRPM/metabolismo , Animais , Aquaporina 4/genética , Astrócitos/patologia , Edema Encefálico/patologia , Células Cultivadas , Cerebelo/patologia , Chlorocebus aethiops , Modelos Animais de Doenças , Edema/genética , Edema/metabolismo , Fluoresceínas/metabolismo , Humanos , Masculino , Potenciais da Membrana/genética , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Complexos Multiproteicos/genética , Pressão Osmótica/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores de Sulfonilureias/genética , Canais de Cátion TRPM/genética
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