RESUMO
The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.
Assuntos
Predisposição Genética para Doença , Genômica , Hipertensão/genética , Rim/patologia , Processamento Alternativo/genética , Pressão Sanguínea/genética , Metilação de DNA/genética , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genéticaRESUMO
The ability of the parasitic blood fluke Schistosoma mansoni and other parasitic helminths to manipulate host biology is well recognised, but the mechanisms that underpin these phenomena are not well understood. An emerging paradigm is that helminths transfer their biological cargo to host cells by secretion of extracellular vesicles (EVs). Herein, we show that two populations of S. mansoni secreted EVs - exosome-like vesicles (ELVs) and microvesicles (MVs) - are actively internalised in two distinct human cell lines that reflect the resident cell types encountered by the parasite in vivo: human umbilical vein endothelial cells (HUVECs) and THP-1 monocytes. RNA-sequencing of HUVECs co-cultured with S. mansoni ELVs compared with untreated HUVECs revealed differential expression of genes associated with intravascular parasitism, including vascular endothelial contraction, coagulation, arachidonic acid metabolism and immune cell trafficking and signalling. Finally, we show that antibodies raised against recombinant tetraspanin (TSP) proteins from the surface of S. mansoni EVs significantly blocked EV uptake by both HUVECs and THP-1 monocytes whereas pre-immunisation antibodies did not. To our knowledge, this is the first evidence demonstrating the internalisation of secreted EVs from any helminth into vascular endothelial cells, providing novel insight into the potential mechanisms underlying host-schistosome interactions. The ability of anti-TSP antibodies to block vesicle uptake by host target cells further supports the potential of TSPs as promising antigens for an anti-fluke vaccine. It also suggests a potential mechanism whereby the current candidate human schistosomiasis vaccine, Sm-TSP-2, exerts its protective effect in animal models.
Assuntos
Vesículas Extracelulares/imunologia , Expressão Gênica/imunologia , Proteínas de Helminto/imunologia , Proteoma/imunologia , Schistosoma mansoni , Esquistossomose mansoni/imunologia , Animais , Interações Hospedeiro-Parasita/imunologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Schistosoma mansoni/imunologia , Schistosoma mansoni/metabolismo , Células THP-1RESUMO
Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype-Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.
Assuntos
Envelhecimento/genética , Néfrons/patologia , Insuficiência Renal Crônica/genética , Transcriptoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Biologia Computacional , Metilação de DNA/genética , Epigenômica , Feminino , Perfilação da Expressão Gênica , Variação Genética , Taxa de Filtração Glomerular/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lactoferrina/genética , Masculino , Pessoa de Meia-Idade , Muramidase/genética , Néfrons/fisiopatologia , Proteínas Nucleares/genética , RNA-Seq , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologiaRESUMO
Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt.
Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/genética , Perfilação da Expressão Gênica , Genótipo , Humanos , Rim/metabolismo , Rim/patologia , Fenótipo , Insuficiência Renal Crônica/patologiaRESUMO
Essential hypertension (EH) is a complex, polygenic condition with no single causative agent. Despite advances in our understanding of the pathophysiology of EH, hypertension remains one of the world's leading public health problems. Furthermore, there is increasing evidence that epigenetic modifications are as important as genetic predisposition in the development of EH. Indeed, a complex and interactive genetic and environmental system exists to determine an individual's risk of EH. Epigenetics refers to all heritable changes to the regulation of gene expression as well as chromatin remodelling, without involvement of nucleotide sequence changes. Epigenetic modification is recognized as an essential process in biology, but is now being investigated for its role in the development of specific pathologic conditions, including EH. Epigenetic research will provide insights into the pathogenesis of blood pressure regulation that cannot be explained by classic Mendelian inheritance. This review concentrates on epigenetic modifications to DNA structure, including the influence of non-coding RNAs on hypertension development.