RESUMO
[Figure: see text].
Assuntos
Apolipoproteína L1/genética , Negro ou Afro-Americano/genética , Doença da Artéria Coronariana/genética , Trombose Coronária/genética , Variação Genética , Placa Aterosclerótica , Adulto , Autopsia , Causas de Morte , Doença da Artéria Coronariana/etnologia , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/patologia , Trombose Coronária/etnologia , Trombose Coronária/mortalidade , Trombose Coronária/patologia , Morte Súbita Cardíaca/etnologia , Morte Súbita Cardíaca/patologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Maryland/epidemiologia , Pessoa de Meia-Idade , Necrose , Fenótipo , Sistema de Registros , Medição de Risco , Fatores de Risco , Ruptura EspontâneaRESUMO
BACKGROUND: Apolipoprotein L1, APOL1, is a trypanosome lytic factor present in human and certain other primates. APOL1 gene variants, present in individuals of recent sub-Saharan African descent, increase risk for glomerular disease and associate with the disease progression, but the molecular mechanisms have not been defined. OBJECTIVES: We focus on the mechanism how APOL1 variant proteins enhance podocyte injury in the stressed kidney. METHODS: First, we investigated the expression of APOL1 protein isoform and the localization of APOL1 protein in the kidney. Next, we examined the role of APOL1 in the podocyte stress and the inflammatory signaling in the kidney after hemi-nephrectomy. RESULTS: We identified a novel RNA variant that lacks a secretory pathway signal sequence and we found that the predicted APOL1-B3 protein isoform was expressed in human podocytes in vivo and by BAC-APOL1 transgenic mice. APOL1-B3-G2 transgenic mice, carrying a renal risk variant, manifested podocyte injury and increased pro-IL-1ß mRNA in isolated glomeruli and increased IL-1ß production in the remnant kidney after uninephrectomy. APOL1-B3 interacted with NLRP12, a key regulator of Toll-like receptor signaling. CONCLUSIONS: These results suggest a possible mechanism for podocyte injury by which one of the APOL1 protein isoforms, APOL1-B3 and its renal risk variants, enhances inflammatory signaling.
Assuntos
Apolipoproteína L1/genética , Inflamação/genética , Glomérulos Renais/metabolismo , Nefrectomia , Podócitos/metabolismo , RNA Mensageiro/metabolismo , Estresse Fisiológico/genética , Animais , Apolipoproteína L1/metabolismo , Humanos , Técnicas In Vitro , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Glomérulos Renais/patologia , Camundongos , Camundongos Transgênicos , Podócitos/patologia , Isoformas de ProteínasRESUMO
Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated with several glycemic and metabolic traits in genome-wide association studies (GWAS). Here, we demonstrate that in humans, FAM13A alleles are associated with increased FAM13A expression in subcutaneous adipose tissue (SAT) and an insulin resistance-related phenotype (e.g. higher waist-to-hip ratio and fasting insulin levels, but lower body fat). In human adipocyte models, knockdown of FAM13A in preadipocytes accelerates adipocyte differentiation. In mice, Fam13a knockout (KO) have a lower visceral to subcutaneous fat (VAT/SAT) ratio after high-fat diet challenge, in comparison to their wild-type counterparts. Subcutaneous adipocytes in KO mice show a size distribution shift toward an increased number of smaller adipocytes, along with an improved adipogenic potential. Our results indicate that GWAS-associated variants within the FAM13A locus alter adipose FAM13A expression, which in turn, regulates adipocyte differentiation and contribute to changes in body fat distribution.
Assuntos
Adipócitos/metabolismo , Distribuição da Gordura Corporal , Proteínas Ativadoras de GTPase/genética , Adipogenia/genética , Animais , Diferenciação Celular/genética , Proteínas Ativadoras de GTPase/metabolismo , Técnicas de Silenciamento de Genes , Loci Gênicos , Estudo de Associação Genômica Ampla , Células HEK293 , Humanos , Resistência à Insulina/genética , Gordura Intra-Abdominal/metabolismo , Masculino , Metabolômica , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Gordura Subcutânea/metabolismoRESUMO
The renal outer medullary potassium channel (ROMK, KCNJ1) mediates potassium recycling and facilitates sodium reabsorption through the Na(+)/K(+)/2Cl(-) cotransporter in the loop of Henle and potassium secretion at the cortical collecting duct. Human genetic studies indicate that ROMK homozygous loss-of-function mutations cause type II Bartter syndrome, featuring polyuria, renal salt wasting, and hypotension; humans heterozygous for ROMK mutations identified in the Framingham Heart Study have reduced blood pressure. ROMK null mice recapitulate many of the features of type II Bartter syndrome. We have generated an ROMK knockout rat model in Dahl salt-sensitive background by using zinc finger nuclease technology and investigated the effects of knocking out ROMK on systemic and renal hemodynamics and kidney histology in the Dahl salt-sensitive rats. The ROMK(-/-) pups recapitulated features identified in the ROMK null mice. The ROMK(+/-) rats, when challenged with a 4% salt diet, exhibited a reduced blood pressure compared with their ROMK(+/+) littermates. More importantly, when challenged with an 8% salt diet, the Dahl salt-sensitive rats with 50% less ROMK expression showed increased protection from salt-induced blood pressure elevation and signs of protection from renal injury. Our findings in ROMK knockout Dahl salt-sensitive rats, together with the previous reports in humans and mice, underscore a critical role of ROMK in blood pressure regulation.
Assuntos
Pressão Sanguínea , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Animais , Feminino , Heterozigoto , Rim/fisiologia , Masculino , Fenótipo , Canais de Potássio Corretores do Fluxo de Internalização/genética , Ratos , Ratos Endogâmicos Dahl , Simportadores de Cloreto de Sódio-Potássio/fisiologia , Membro 1 da Família 12 de Carreador de SolutoRESUMO
In investigation of the genetic characteristics of rabies viruses in Korea, the nucleotide and deduced amino acid sequences of the nucleoprotein (N) gene were determined in four Korean rabies virus strains obtained from dogs and raccoons, and were compared with published sequences for non-Korean rabies viruses. Three Korean rabies virus isolates had identical nucleotide sequences, and the fourth differed at only one nucleotide position. The Korean virus isolates had 84.5-92.0% nucleotide sequence similarity and 94.0-99.2% amino acid sequence similarity with non-Korean rabies virus isolates. In a phylogenetic tree based on partial nucleotide sequences of the N gene, the Korean rabies viruses formed a single cluster closely related to Arctic rabies viruses (FXCAN, 9141RUS, and 94260NEP). However, they were divergent from other Asian rabies viruses (94256SRL, 8677MAL, ChiNo.7, Phil 12301, and Mdn1278).
