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1.
Sci Transl Med ; 15(698): eabn0736, 2023 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-37256934

RESUMO

Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1+) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1+ cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1+ cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell-resolution transcriptomic analysis, we identified an "inflammatory" proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)-induced IHH production in vivo. TNF-induced Ubiquitin D (Ubd) expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1+ cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by Ihh deletion in Pax8-expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1+ cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis.


Assuntos
Proteínas Hedgehog , Insuficiência Renal Crônica , Animais , Humanos , Camundongos , Fibrose , Proteínas Hedgehog/metabolismo , Inflamação , NF-kappa B , Fatores de Necrose Tumoral , Proteína GLI1 em Dedos de Zinco
2.
JCI Insight ; 5(24)2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33328386

RESUMO

Small noncoding RNAs, miRNAs (miRNAs), are emerging as important modulators in the pathogenesis of kidney disease, with potential as biomarkers of kidney disease onset, progression, or therapeutic efficacy. Bulk tissue small RNA-sequencing (sRNA-Seq) and microarrays are widely used to identify dysregulated miRNA expression but are limited by the lack of precision regarding the cellular origin of the miRNA. In this study, we performed cell-specific sRNA-Seq on tubular cells, endothelial cells, PDGFR-ß+ cells, and macrophages isolated from injured and repairing kidneys in the murine reversible unilateral ureteric obstruction model. We devised an unbiased bioinformatics pipeline to define the miRNA enrichment within these cell populations, constructing a miRNA catalog of injury and repair. Our analysis revealed that a significant proportion of cell-specific miRNAs in healthy animals were no longer specific following injury. We then applied this knowledge of the relative cell specificity of miRNAs to deconvolute bulk miRNA expression profiles in the renal cortex in murine models and human kidney disease. Finally, we used our data-driven approach to rationally select macrophage-enriched miR-16-5p and miR-18a-5p and demonstrate that they are promising urinary biomarkers of acute kidney injury in renal transplant recipients.


Assuntos
Injúria Renal Aguda/genética , MicroRNAs/genética , Especificidade de Órgãos/genética , Animais , Biomarcadores , Biologia Computacional/métodos , Células Endoteliais/metabolismo , Perfilação da Expressão Gênica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Rim/metabolismo , Túbulos Renais/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo
3.
Front Physiol ; 10: 1365, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803059

RESUMO

Chronic kidney disease (CKD) is prevalent worldwide and is associated with significant co-morbidities including cardiovascular disease (CVD). Traditionally, the subtotal nephrectomy (remnant kidney) experimental model has been performed in rats to model progressive renal disease. The model experimentally mimics CKD by reducing nephron number, resulting in renal insufficiency. Presently, there is a lack of translation of pre-clinical findings into successful clinical results. The pre-clinical nephrology field would benefit from reproducible progressive renal disease models in mice in order to avail of more widely available transgenics and experimental tools to dissect mechanisms of disease. Here we evaluate if a simplified single step subtotal nephrectomy (STNx) model performed in the 129S2/SV mouse can recapitulate the renal and cardiac changes observed in patients with CKD in a reproducible and robust way. The single step STNx surgery was well-tolerated and resulted in clinically relevant outcomes including hypertension, increased urinary albumin:creatinine ratio, and significantly increased serum creatinine, phosphate and urea. STNx mice developed significant left ventricular hypertrophy without reduced ejection fraction or cardiac fibrosis. Analysis of intra-renal inflammation revealed persistent recruitment of Ly6C hi monocytes transitioning to pro-fibrotic inflammatory macrophages in STNx kidneys. Unlike 129S2/SV mice, C57BL/6 mice exhibited renal fibrosis without proteinuria, renal dysfunction, or cardiac pathology. Therefore, the 129S2/SV genetic background is susceptible to induction of progressive proteinuric renal disease and cardiac hypertrophy using our refined, single-step flank STNx method. This reproducible model could be used to study the systemic pathophysiological changes induced by CKD in the kidney and the heart, intra-renal inflammation and for testing new therapies for CKD.

4.
J Fam Plann Reprod Health Care ; 32(1): 15-8, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16492327

RESUMO

OBJECTIVE: Secondary care services are struggling to manage demand for induced abortion, but less is known about what scope exists to improve the primary care of women requiring abortion. The study objective was to identify service-related delays and barriers faced by women seeking abortion care. METHODS: The study comprised case note review and cross-sectional surveys conducted in South Durham in the North East of England, UK. We surveyed and reviewed the case notes of women attending two fertility control clinics. We also surveyed general practitioners (GPs) who referred women to these clinics. The outcomes were waiting times within the pathway to induced abortion, women's rating of care, GPs' attitudes and self-reported practice. RESULTS: Of 210 women surveyed, 132 (63%) responded. Of 107 referred by GPs, 16 (15%) had to make a second appointment with another GP willing to refer them and 34 (32%) waited two or more days to receive a date for their hospital appointment. The national standard waiting time of 3 weeks from first appointment with the referring doctor to the procedure was achieved for 56/127 women (44%; 95% CI, 35-53). Women rated global satisfaction, provision of information and staff interaction more highly in secondary than primary care. Of 170 GPs surveyed, 140 (82%) responded; 33 (24%) considered themselves 'broadly anti-abortion'. CONCLUSIONS: Women face delays in accessing induced abortion care, both before and after referral from primary care. Whilst scope exists for improving quality of care and access within present service configurations, alternative approaches that bypass traditional gatekeepers to abortion care should be evaluated.


Assuntos
Aborto Induzido , Atitude do Pessoal de Saúde , Médicos de Família/psicologia , Adulto , Estudos Transversais , Inglaterra , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Gravidez
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