RESUMO
Kidneys have a high energy demand to facilitate the reabsorption of the glomerular filtrate. For this reason, renal cells have a high density of mitochondria. Mitochondrial cytopathies can be the result of a mutation in both mitochondrial and nuclear DNA. Mitochondrial dysfunction can lead to a variety of renal manifestations. Examples of tubular manifestations are renal Fanconi Syndrome, which is often found in patients diagnosed with Kearns-Sayre and Pearson's marrow-pancreas syndrome, and distal tubulopathies, which result in electrolyte disturbances such as hypomagnesemia. Nephrotic syndrome can be a glomerular manifestation of mitochondrial dysfunction and is typically associated with focal segmental glomerular sclerosis on histology. Tubulointerstitial nephritis can also be seen in mitochondrial cytopathies and may lead to end-stage renal disease. The underlying mechanisms of these cytopathies remain incompletely understood; therefore, current therapies focus mainly on symptom relief. A better understanding of the molecular disease mechanisms is critical in order to improve treatments.
Assuntos
Mutação , DNA Mitocondrial/genética , Humanos , Síndrome de Kearns-Sayre , Mitocôndrias/genética , Miopatias Mitocondriais , Nefrite IntersticialRESUMO
The pathogenesis of parathyroid gland hyperplasia is poorly understood, and a better understanding is essential if there is to be improvement over the current strategies for prevention and treatment of secondary hyperparathyroidism. Here we investigate the specific role of Klotho expressed in the parathyroid glands (PTGs) in mediating parathyroid hormone (PTH) and serum calcium homeostasis, as well as the potential interaction between calcium-sensing receptor (CaSR) and Klotho. We generated mouse strains with PTG-specific deletion of Klotho and CaSR and dual deletion of both genes. We show that ablating CaSR in the PTGs increases PTH synthesis, that Klotho has a pivotal role in suppressing PTH in the absence of CaSR, and that CaSR together with Klotho regulates PTH biosynthesis and PTG growth. We utilized the tdTomato gene in our mice to visualize and collect PTGs to reveal an inhibitory function of Klotho on PTG cell proliferation. Chronic hypocalcemia and ex vivo PTG culture demonstrated an independent role for Klotho in mediating PTH secretion. Moreover, we identify an interaction between PTG-expressed CaSR and Klotho. These findings reveal essential and interrelated functions for CaSR and Klotho during parathyroid hyperplasia.
Assuntos
Glucuronidase/fisiologia , Glândulas Paratireoides/metabolismo , Hormônio Paratireóideo/biossíntese , Receptores Acoplados a Proteínas G/fisiologia , Animais , Osso e Ossos/patologia , Cálcio/metabolismo , Cálcio da Dieta/administração & dosagem , Feminino , Fator de Crescimento de Fibroblastos 23 , Glucuronidase/deficiência , Glucuronidase/genética , Homeostase , Hipercalcemia/genética , Hipercalcemia/patologia , Hiperparatireoidismo/genética , Hiperparatireoidismo/patologia , Hiperplasia , Hipocalcemia/metabolismo , Hipofosfatemia/genética , Hipofosfatemia/patologia , Imunoprecipitação , Rim/patologia , Proteínas Klotho , Masculino , Camundongos , Glândulas Paratireoides/patologia , Hormônio Paratireóideo/genética , Mapeamento de Interação de Proteínas , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Detecção de Cálcio , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/genéticaRESUMO
Renal Ca2+ reabsorption is essential for maintaining systemic Ca2+ homeostasis and is tightly regulated through the parathyroid hormone (PTH)/PTHrP receptor (PTH1R) signaling pathway. We investigated the role of PTH1R in the kidney by generating a mouse model with targeted deletion of PTH1R in the thick ascending limb of Henle (TAL) and in distal convoluted tubules (DCTs): Ksp-cre;Pth1rfl/fl Mutant mice exhibited hypercalciuria and had lower serum calcium and markedly increased serum PTH levels. Unexpectedly, proteins involved in transcellular Ca2+ reabsorption in DCTs were not decreased. However, claudin14 (Cldn14), an inhibitory factor of the paracellular Ca2+ transport in the TAL, was significantly increased. Analyses by flow cytometry as well as the use of Cldn14-lacZ knock-in reporter mice confirmed increased Cldn14 expression and promoter activity in the TAL of Ksp-cre;Pth1rfl/fl mice. Moreover, PTH treatment of HEK293 cells stably transfected with CLDN14-GFP, together with PTH1R, induced cytosolic translocation of CLDN14 from the tight junction. Furthermore, mice with high serum PTH levels, regardless of high or low serum calcium, demonstrated that PTH/PTH1R signaling exerts a suppressive effect on Cldn14. We therefore conclude that PTH1R signaling directly and indirectly regulates the paracellular Ca2+ transport pathway by modulating Cldn14 expression in the TAL. Finally, systemic deletion of Cldn14 completely rescued the hypercalciuric and lower serum calcium phenotype in Ksp-cre;Pth1rfl/fl mice, emphasizing the importance of PTH in inhibiting Cldn14. Consequently, suppressing CLDN14 could provide a potential treatment to correct urinary Ca2+ loss, particularly in patients with hypoparathyroidism.
Assuntos
Cálcio/metabolismo , Claudinas/fisiologia , Extremidades/fisiologia , Regulação da Expressão Gênica , Hormônio Paratireóideo/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Junções Íntimas/fisiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regiões Promotoras Genéticas/genética , Transdução de SinaisRESUMO
BACKGROUND: Protein-losing enteropathy (PLE) is a severe complication of Fontan circulation with increased risk of end-organ dysfunction. We evaluated tissue oxygenation via near-infrared spectroscopy (NIRS) at different exercise levels in Fontan patients. METHODS: Assessment of multisite NIRS during cycle ergometer exercise and daily activities in three groups: Fontan patients with PLE; without PLE; patients with dextro-transposition of the great arteries (d-TGA); comparing univentricular with biventricular circulation and Fontan with/without PLE. Renal threshold analysis (<65%;<55%;<45%) of regional oxygen saturation (rSO2) was performed. RESULTS: Fontan patients showed reduced rSO2 (p < 0.05) in their quadriceps femoris muscle compared with biventricular d-TGA patients at all time points. rSO2 in renal tissue was reduced at baseline (p = 0.002), exercise (p = 0.0062), and daily activities (p = 0.03) in Fontan patients with PLE. Renal threshold analysis identified critically low renal rSO2 (rSO2 < 65%) in Fontan patients with PLE during exercise (95% of monitoring time below threshold) and daily activities (83.7% time below threshold). CONCLUSION: Fontan circulation is associated with decreased rSO2 values in skeletal muscle and hypoxemia of renal tissue solely in patients with PLE. Reduced rSO2 already during activities of daily life, might contribute to comorbidities in patients with Fontan circulation, including PLE and renal failure.
Assuntos
Técnica de Fontan/efeitos adversos , Oxigênio/metabolismo , Enteropatias Perdedoras de Proteínas/etiologia , Enteropatias Perdedoras de Proteínas/metabolismo , Adolescente , Encéfalo/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Exercício Físico/fisiologia , Humanos , Hipóxia/etiologia , Hipóxia/metabolismo , Lactente , Rim/lesões , Rim/metabolismo , Músculo Esquelético/metabolismo , Oxigênio/sangue , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/metabolismo , Espectroscopia de Luz Próxima ao Infravermelho , Transposição dos Grandes Vasos/cirurgia , Coração Univentricular/cirurgia , Adulto JovemRESUMO
Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.
Assuntos
Proteínas de Transporte/genética , Proteínas Culina/genética , Hipertensão/genética , Mutação/genética , Pseudo-Hipoaldosteronismo/genética , Desequilíbrio Hidroeletrolítico/genética , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Animais , Sequência de Bases , Pressão Sanguínea/genética , Proteínas de Transporte/química , Estudos de Coortes , Proteínas Culina/química , Eletrólitos , Éxons/genética , Feminino , Perfilação da Expressão Gênica , Genes Dominantes/genética , Genes Recessivos/genética , Genótipo , Homeostase/genética , Humanos , Concentração de Íons de Hidrogênio , Hipertensão/complicações , Hipertensão/fisiopatologia , Masculino , Camundongos , Proteínas dos Microfilamentos , Modelos Moleculares , Dados de Sequência Molecular , Fenótipo , Potássio/metabolismo , Pseudo-Hipoaldosteronismo/complicações , Pseudo-Hipoaldosteronismo/fisiopatologia , Cloreto de Sódio/metabolismo , Desequilíbrio Hidroeletrolítico/complicações , Desequilíbrio Hidroeletrolítico/fisiopatologiaRESUMO
In addition to its prominent role in the parathyroid gland, the calcium-sensing receptor (CaSR) is expressed in various tissues, including the kidney. This article reviews current data on the calcium-sensing properties of the kidney, the localization of the CaSR protein along the nephron, and its function in calcium homeostasis and in hypercalciuria.
Assuntos
Cálcio/metabolismo , Túbulos Renais/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Animais , Homeostase , Humanos , Hipercalciúria/metabolismo , Hipercalciúria/fisiopatologia , Túbulos Renais/fisiopatologia , Transdução de SinaisRESUMO
FSGS is characterized by the presence of partial sclerosis of some but not all glomeruli. Studies of familial FSGS have been instrumental in identifying podocytes as critical elements in maintaining glomerular function, but underlying mutations have not been identified for all forms of this genetically heterogeneous condition. Here, exome sequencing in members of an index family with dominant FSGS revealed a nonconservative, disease-segregating variant in the PAX2 transcription factor gene. Sequencing in probands of a familial FSGS cohort revealed seven rare and private heterozygous single nucleotide substitutions (4% of individuals). Further sequencing revealed seven private missense variants (8%) in a cohort of individuals with congenital abnormalities of the kidney and urinary tract. As predicted by in silico structural modeling analyses, in vitro functional studies documented that several of the FSGS-associated PAX2 mutations perturb protein function by affecting proper binding to DNA and transactivation activity or by altering the interaction of PAX2 with repressor proteins, resulting in enhanced repressor activity. Thus, mutations in PAX2 may contribute to adult-onset FSGS in the absence of overt extrarenal manifestations. These results expand the phenotypic spectrum associated with PAX2 mutations, which have been shown to lead to congenital abnormalities of the kidney and urinary tract as part of papillorenal syndrome. Moreover, these results indicate PAX2 mutations can cause disease through haploinsufficiency and dominant negative effects, which could have implications for tailoring individualized drug therapy in the future.
Assuntos
Glomerulosclerose Segmentar e Focal/genética , Mutação , Fator de Transcrição PAX2/genética , Adolescente , Adulto , Idade de Início , Idoso , Sequência de Aminoácidos , Sequência de Bases , Estudos de Coortes , Simulação por Computador , Sequência Conservada , Análise Mutacional de DNA , Exoma , Feminino , Glomerulosclerose Segmentar e Focal/metabolismo , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Fator de Transcrição PAX2/química , Fator de Transcrição PAX2/metabolismo , Linhagem , Polimorfismo de Nucleotídeo Único , Conformação Proteica , Eletricidade Estática , Anormalidades Urogenitais , Refluxo Vesicoureteral/genética , Adulto JovemRESUMO
The mechanisms that govern homeostasis of complex systems have been elusive but can be illuminated by mutations that disrupt system behavior. Mutations in the gene encoding the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and hyperkalemia. We show that physiology in mice transgenic for genomic segments harboring wild-type (TgWnk4(WT)) or PHAII mutant (TgWnk4(PHAII)) Wnk4 is changed in opposite directions: TgWnk4(PHAII) mice have higher blood pressure, hyperkalemia, hypercalciuria and marked hyperplasia of the distal convoluted tubule (DCT), whereas the opposite is true in TgWnk4(WT) mice. Genetic deficiency for the Na-Cl cotransporter of the DCT (NCC) reverses phenotypes seen in TgWnk4(PHAII) mice, demonstrating that the effects of the PHAII mutation are due to altered NCC activity. These findings establish that Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K+ secretion by altering the mass and function of the DCT through its effect on NCC.
Assuntos
Pressão Sanguínea/fisiologia , Túbulos Renais Distais/metabolismo , Potássio/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Cromossomos Artificiais Bacterianos , Eletrólitos/sangue , Feminino , Homeostase , Humanos , Túbulos Renais Distais/diagnóstico por imagem , Camundongos , Camundongos Transgênicos , Mutação , Pseudo-Hipoaldosteronismo/genética , Simportadores de Cloreto de Sódio/genética , Simportadores de Cloreto de Sódio/metabolismo , UltrassonografiaRESUMO
PURPOSE OF REVIEW: Variations in extracellular calcium level have a large impact on kidney function. Most of the effects seen are attributed to the calcium-sensing receptor (CaSR), a widely expressed G-protein-coupled cell surface protein with an important function in bone mineral homeostasis. The purpose of this review is to recapitulate the novel functional aspects of CaSR. RECENT FINDINGS: Results from mouse models demonstrate important functions for CaSR in various tissues. In the kidney, the main role of CaSR is the regulation of calcium reabsorption in the thick ascending limb, independently of its role on parathyroid hormone secretion. CaSR modulates claudin 14, the gatekeeper of paracellular ion transport in the thick ascending limb that is associated with urinary calcium excretion. One intracellular signaling pathway by which CaSR alters tight junction permeability is the calcineurin-NFAT1c-microRNA-claudin14 axis. SUMMARY: The main function of CaSR in the kidney is the regulation of calcium excretion in the thick ascending limb, independently of parathyroid hormone. CaSR modulates paracellular cation transport by altering expression of the tight junction protein claudin 14. Still more work is needed to fully understand all functions of CaSR in the kidney. Alternative pathways of calcium 'sensing' in the kidney need to be investigated.
Assuntos
Cálcio/metabolismo , Rim/metabolismo , Receptores de Detecção de Cálcio/genética , Receptores de Detecção de Cálcio/metabolismo , Junções Íntimas/metabolismo , Animais , Cálcio/urina , Claudinas/metabolismo , Homeostase , Humanos , Hipercalcemia/congênito , Hipercalcemia/genética , Hiperparatireoidismo/genética , Camundongos , Modelos Animais , Permeabilidade , Transdução de SinaisRESUMO
PURPOSE OF REVIEW: The calcium-sensing receptor (CaSR) has a central role in parathyroid gland function. Genetic alterations in CaSR are well known to cause inherited forms of abnormal calcium homeostasis. This review focuses on studies investigating the role of CaSR in common disorders of abnormal calcium handling and in cardiovascular calcification. RECENT FINDINGS: Genetic population studies tested the association of common allelic CASR variants with serum and urine calcium levels, kidney stone disease, primary hyperparathyroidism and bone mineral density. The results of these association studies suggested either minor or no effects of CASR variants in these phenotypes. Decreased expression of CaSR was associated with the etiology of cardiovascular calcification in individuals with advanced chronic kidney disease. SUMMARY: Ionized calcium plays a central role in the physiology of many organ systems and disease states, but the roles of CaSR other than as illustrated by Mendelian forms of CaSR dysfunction remain unclear. The contributions of CaSR to bone mineral homeostasis, vascular calcification and other forms of cardiovascular disease need further investigation.
Assuntos
Cálcio/metabolismo , Doenças Cardiovasculares/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Animais , Remodelação Óssea , Sinalização do Cálcio , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Predisposição Genética para Doença , Homeostase , Humanos , Hipercalcemia/genética , Hipercalcemia/metabolismo , Hipercalcemia/fisiopatologia , Hipercalciúria/genética , Hipercalciúria/metabolismo , Hipercalciúria/fisiopatologia , Cálculos Renais/genética , Cálculos Renais/metabolismo , Cálculos Renais/fisiopatologia , Mutação , Fenótipo , Receptores de Detecção de Cálcio/genética , Calcificação Vascular/genética , Calcificação Vascular/metabolismo , Calcificação Vascular/fisiopatologiaRESUMO
Brachydactyly type E (BDE), shortened metacarpals, metatarsals, cone-shaped epiphyses, and short stature commonly occurs as a sole phenotype. Parathyroid hormone-like protein (PTHrP) has been shown to be responsible in all forms to date, either directly or indirectly. We used linkage and then whole genome sequencing in a small pedigree, to elucidate BDE and identified a truncated disintegrin-and-metalloproteinase-19 (ADAM19) allele in all affected family members, but not in nonaffected persons. Since we had shown earlier that the extracellular domain of the parathyroid hormone receptor (PTHR1) is subject to an unidentified metalloproteinase cleavage, we tested the hypothesis that ADAM19 is a sheddase for PTHR1. WT ADAM19 cleaved PTHR1, while mutated ADAM-19 did not. We mapped the cleavage site that we verified with mass spectrometry between amino acids 64-65. ADAM-19 cleavage increased Gq and decreased Gs activation. Moreover, perturbed PTHR1 cleavage by ADAM19 increased ß-arrestin2 recruitment, while cAMP accumulation was not altered. We suggest that ADAM19 serves as a regulatory element for PTHR1 and could be responsible for BDE. This sheddase may affect other PTHrP or PTH-related functions.
Assuntos
Braquidactilia , Proteína Relacionada ao Hormônio Paratireóideo , Humanos , Proteína Relacionada ao Hormônio Paratireóideo/genética , Braquidactilia/genética , Receptor Tipo 1 de Hormônio Paratireóideo/genética , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Metaloproteases , Proteínas ADAMRESUMO
A pregnant woman presented at gestational week 28 with loss of consciousness and profound polyuria. Further characterization revealed osmotic diuresis due to massive glycosuria without hyperglycemia. Glycosuria reduced substantially postpartum, from approximately 100 to approximately 30 g/1.73 m2 per day. DNA sequencing analysis of the SLC5A2 gene encoding the renal glucose transporter SGLT2 showed a homozygous frame-shift mutation (occurring after the glutamine at amino acid 168 and leading to premature termination of the protein at amino acid 186) diagnostic of familial renal glycosuria. Pregnant women with familial renal glycosuria can be at risk of profound polyuria during pregnancy due to the associated increase in glycosuria. These findings also have implications for the use of SGLT2 inhibitors in clinical practice.
Assuntos
Glicosúria Renal/genética , Poliúria/genética , Complicações na Gravidez/genética , Adulto , Diagnóstico Diferencial , Feminino , Mutação da Fase de Leitura/genética , Intolerância à Glucose/diagnóstico , Intolerância à Glucose/genética , Glicosúria Renal/diagnóstico , Homozigoto , Humanos , Testes de Função Renal , Gravidez , Complicações na Gravidez/diagnóstico , Segundo Trimestre da Gravidez , Análise de Sequência de DNA , Transportador 2 de Glucose-Sódio/genéticaRESUMO
Advances in genetic mapping and sequencing techniques have led to substantial progress in the study of rare monogenic (Mendelian) forms of abnormal blood pressure. Many disease-defining pathways for hypertension have been identified in the past two decades. Perturbations in renal salt handling appear to be a common mechanism underlying these rare syndromes of hypertension. Excess activation at various points in the mineralocorticoid signaling pathway and malfunctioning of the autonomic (specifically sympathetic) nervous system have both been implicated in inducing hypertension, while complementary studies examining low blood pressure phenotypes have identified novel pathways exclusively linked to renal salt wasting in either the thick ascending limb or the distal nephron. The genetic defects and the physiological and cellular pathways affected in these various disorders are reviewed here. Importantly, studies have suggested that genetic variation affecting these same genes and pathways may play an important role in explaining the variation of blood pressure levels in the general population. The investigation of rare syndromes of human blood pressure variation has important implications for improving the diagnosis and treatment of hypertension.
Assuntos
Pressão Sanguínea/genética , Hipertensão/genética , Hipotensão/genética , Rim/fisiopatologia , Erros Inatos do Transporte Tubular Renal/genética , Animais , Predisposição Genética para Doença , Humanos , Hipertensão/diagnóstico , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Hipertensão/terapia , Hipotensão/diagnóstico , Hipotensão/metabolismo , Hipotensão/fisiopatologia , Hipotensão/terapia , Rim/metabolismo , Fenótipo , Prognóstico , Erros Inatos do Transporte Tubular Renal/diagnóstico , Erros Inatos do Transporte Tubular Renal/metabolismo , Erros Inatos do Transporte Tubular Renal/fisiopatologia , Erros Inatos do Transporte Tubular Renal/terapiaRESUMO
Rare loss-of-function mutations in the calcium-sensing receptor (Casr) gene lead to decreased urinary calcium excretion in the context of parathyroid hormone (PTH)-dependent hypercalcemia, but the role of Casr in the kidney is unknown. Using animals expressing Cre recombinase driven by the Six2 promoter, we generated mice that appeared grossly normal but had undetectable levels of Casr mRNA and protein in the kidney. Baseline serum calcium, phosphorus, magnesium, and PTH levels were similar to control mice. When challenged with dietary calcium supplementation, however, these mice had significantly lower urinary calcium excretion than controls (urinary calcium to creatinine, 0.31±0.03 versus 0.63±0.14; P=0.001). Western blot analysis on whole-kidney lysates suggested an approximately four-fold increase in activated Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). In addition, experimental animals exhibited significant downregulation of Claudin14, a negative regulator of paracellular cation permeability in the thick ascending limb, and small but significant upregulation of Claudin16, a positive regulator of paracellular cation permeability. Taken together, these data suggest that renal Casr regulates calcium reabsorption in the thick ascending limb, independent of any change in PTH, by increasing the lumen-positive driving force for paracellular Ca(2+) transport.
Assuntos
Cálcio/urina , Rim/metabolismo , Receptores de Detecção de Cálcio/deficiência , Animais , Sequência de Bases , Claudinas/metabolismo , Proteínas de Homeodomínio/genética , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hormônio Paratireóideo/metabolismo , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Detecção de Cálcio/genética , Simportadores de Cloreto de Sódio-Potássio/metabolismo , Membro 1 da Família 12 de Carreador de Soluto , Fatores de Transcrição/genéticaRESUMO
Infective endocarditis (IE) is more common in patients with predisposing cardiac lesions and has many potential complications, including stroke and arterial thromboembolisms. Renal manifestations have an estimated prevalence of â¼20%. Rapidly progressive glomerulonephritis (RPGN) is a nephrological emergency manifested by autoimmune-mediated progressive loss of renal function over a relatively short period of time. Here, we report the case of a 60-year-old Caucasian male, who presented with speech impairment and was found to have multiple embolic strokes caused by aortic valve IE. His renal function declined rapidly, and his urine sediment featured hematuria and proteinuria. ANCA titer was negative by immunofluorescence (IF); however, the PR3 antibody was elevated. The renal biopsy revealed pauci-immune focally necrotizing glomerulonephritis with the presence of â¼25% cellular crescents. He was initially treated with plasmapheresis and pulse dose steroids. Hemodialysis was initiated for uremic symptoms. After four weeks of antibiotic therapy and with blood cultures remaining negative, he was treated with rituximab. Two months after discharge, his renal function showed improvement, and hemodialysis was discontinued. This case highlights several complications associated with lactobacillus endocarditis including RPGN.
RESUMO
Autosomal-dominant hypertension with brachydactyly is a salt-independent Mendelian syndrome caused by activating mutations in the gene encoding phosphodiesterase 3A. These mutations increase the protein kinase A-mediated phosphorylation of phosphodiesterase 3A resulting in enhanced cAMP-hydrolytic affinity and accelerated cell proliferation. The phosphorylated vasodilator-stimulated phosphoprotein is diminished, and parathyroid hormone-related peptide is dysregulated, potentially accounting for all phenotypic features. Untreated patients die prematurely of stroke; however, hypertension-induced target-organ damage is otherwise hardly apparent. We conducted clinical studies of vascular function, cardiac functional imaging, platelet function in affected and nonaffected persons, and cell-based assays. Large-vessel and cardiac functions indeed seem to be preserved. The platelet studies showed normal platelet function. Cell-based studies demonstrated that available phosphodiesterase 3A inhibitors suppress the mutant isoforms. However, increasing cGMP to indirectly inhibit the enzyme seemed to have particular use. Our results shed more light on phosphodiesterase 3A activation and could be relevant to the treatment of severe hypertension in the general population.
Assuntos
Braquidactilia/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , DNA/genética , Hipertensão/congênito , Mutação , Adolescente , Adulto , Pressão Sanguínea/fisiologia , Braquidactilia/diagnóstico , Braquidactilia/enzimologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Análise Mutacional de DNA , Ecocardiografia Doppler de Pulso , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/enzimologia , Hipertensão/genética , Immunoblotting , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB). The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated. In vitro analyses of mesenchymal stem cell-derived vascular smooth muscle cells (VSMCs) and chondrocytes provided insights into molecular pathogenesis. The mutations increased protein kinase A-mediated PDE3A phosphorylation and resulted in gain of function, with increased cAMP-hydrolytic activity and enhanced cell proliferation. Levels of phosphorylated VASP were diminished, and PTHrP levels were dysregulated. We suggest that the identified PDE3A mutations cause the syndrome. VSMC-expressed PDE3A deserves scrutiny as a therapeutic target for the treatment of hypertension.
Assuntos
Braquidactilia/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Hipertensão/congênito , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Sequência de Bases , Estudos de Casos e Controles , Diferenciação Celular , Criança , Feminino , Estudos de Associação Genética , Células HeLa , Humanos , Hipertensão/genética , Cinética , Masculino , Células-Tronco Mesenquimais/fisiologia , Camundongos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Miócitos de Músculo Liso/fisiologia , LinhagemRESUMO
OBJECTIVE: Brainstem neurovascular contact (NVC) may interfere with central autonomic regulation and contribute to essential hypertension. We have previously shown that patients with autosomal-dominant hypertension, brachydactyly, and NVC feature extreme phenylephrine hypersensitivity due to impaired baroreflex buffering. We tested the hypothesis that similar abnormalities are present in patients with essential hypertension who have NVC. METHODS: Six patients with NVC and essential hypertension and five patients with NVC and monogenic hypertension and brachydactyly were studied. Responses to incremental phenylephrine doses were assessed before and during ganglionic blockade with trimethaphan. RESULTS: Supine blood pressure was 172 +/- 8.8/89 +/- 6.1 mmHg before ganglionic blockade. Blood pressure decreased 47 +/- 5/18 +/- 3 mmHg with trimethaphan (16 +/- 4.4/4 +/- 4.0 mmHg in autosomal-dominant hypertension, P < 0.05). Before ganglionic blockade, 25 microg phenylephrine increased systolic blood pressure 17 +/- 4 mmHg in patients with essential hypertension and 30 +/- 3 mmHg in patients with autosomal-dominant hypertension (P < 0.05). During ganglionic blockade, the same dose increased systolic blood pressure 32 +/- 1 and 33 +/- 4 mmHg in patients with essential and with autosomal-dominant hypertension, respectively (NS). CONCLUSIONS: Phenylephrine hypersensitivity due to baroreflex dysfunction is uncommon in patients with essential hypertension and NVC. This finding may suggest that the effect of NVC on autonomic regulation is heterogeneous. An alternative explanation is that radiological NVC is not necessarily functionally relevant.
Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Tronco Encefálico/fisiopatologia , Hipertensão/fisiopatologia , Anti-Hipertensivos/farmacologia , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Cerebelo/irrigação sanguínea , Resistência a Medicamentos , Feminino , Bloqueadores Ganglionares/farmacologia , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Masculino , Bulbo/fisiopatologia , Pessoa de Meia-Idade , Modelos Cardiovasculares , Modelos Neurológicos , Fenilefrina/farmacologia , Trimetafano/farmacologiaRESUMO
Monogenic or Mendelian forms of hypertension have ushered in a revolution in our knowledge. If we add information on syndromes involving low blood pressure, this knowledge base is doubled. Glucocorticoid-remediable aldosteronism, apparent mineralocorticoid excess, and mutations in the mineralocorticoid receptor gene have given us brilliant insights into mineralocorticoid-induced hypertension. The latter discovery has elucidated how mutations may modify the receptor sufficiently to allow erstwhile antagonists to have an agonistic action. The epithelial sodium channel (ENaC) has been elucidated. Gain-of-function mutations in the beta and gamma subunits of ENaC cause Liddle's syndrome. Loss-of-function mutations in all 3 subunits of ENaC cause hypotension (pseudohypoaldosteronism type I). Thus, all 3 subunits can be mutated, causing either hyper- or hypotension. Three loci have been described for Gordon's syndrome, pseudohypoaldosteronism type II; 2 members of the WNK (with no ly sine K) serine-threonine kinase family have recently been found to be responsible. Autosomal-dominant hypertension with brachydactyly features normal sodium and renin-angiotensin-aldosterone responses. The gene has been mapped to chromosome 12p. The condition is interesting because it may represent a novel neural form of hypertension. The elucidation of Mendelian blood pressure-regulatory disorders has been a resounding success.
Assuntos
Hiperaldosteronismo/genética , Hipertensão/genética , Pseudo-Hipoaldosteronismo/genética , Receptores de Mineralocorticoides/genética , Humanos , Receptores de Mineralocorticoides/metabolismo , Esteroide 17-alfa-Hidroxilase/genética , SíndromeRESUMO
Hypertension is a substantial public health problem affecting about 25% of the population in industrialized societies. The disorder is responsible for many common causes of morbidity and mortality. Despite the important role of hypertension as a cause of disease, its pathogenesis remains largely unknown. The application of genetic approaches to rare monogenic (Mendelian) forms of hypertension and hypotension has begun to delineate molecular pathways underlying human blood pressure variation, defining disease pathogenesis and identifying targets for therapeutic intervention. In all cases the pathophysiology is altered net renal salt reabsorption. Mutations are either affecting circulating mineralocorticoid hormones or renal ion channels and transporters. Examples are glucocorticoid-remediable aldosteronism (GRA), Liddle's syndrome, the syndrome of hypertension exacerbated in pregnancy, and apparent mineralocorticoid-excess (AME). Recently, alterations in genes of a novel serine-threonine kinase family (WNK1 and WNK4) were identified causing pseudohypoaldosteronism type II. The molecular pathway of this syndrome remains unclear. Additionally, there is the syndrome of hypertension associated with brachydactyly type E (Bilginturan's syndrome), for which the molecular mechanism has yet to be identified.