Loss of HtrA1-induced attenuation of TGF-β signaling in fibroblasts might not be the main mechanism of CARASIL pathogenesis

Liu, Ju; Fang, Dong; Hoh, Josephine

doi:10.1073/pnas.1500911112

Cited by 7 publications

(7 citation statements)

References 5 publications

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“…The frozen samples of mouse kidney were sectioned at 10 mm on aminoalylsilane-coated slides (HistoGene; Arcturus Engineering, Mountain View, CA). Laser capture microdissection (LCM) collection was performed by the Arcturus microdissection system (Life Technologies) (28). Specific tissues were collected by transferring them from tissue sections to an adhesive infrared-activated polymer on the CapSure HS LCM Cap (Life Technologies).…”

Section: Laser Capture Microdissectionmentioning

confidence: 99%

Cadmium Induces Glomerular Endothelial Cell–Specific Expression of Complement Factor H via the −1635 AP-1 Binding Site

Chen

Liu

et al. 2019

The Journal of Immunology

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Cadmium (Cd) is an environmental toxin that induces nephrotoxicity. Complement factor H (CFH), an inhibitor of complement activation, is involved in the pathogenesis of various renal diseases. In this study, we investigated the effects of Cd on CFH production by the kidney. In C57B6/J mice, an increased CFH level was found in renal blood and glomerular endothelial cells after Cd treatment. In vitro, Cd induces an increased CFH secretion and mRNA expression in human renal glomerular endothelial cells but not in human podocytes or human mesangial cells. Cd activates the JNK pathway and increases c-Jun and c-Fos in human renal glomerular endothelial cells. A JNK inhibitor, SP600125, specifically abolishes Cd-induced CFH production. By chromatin immunoprecipitation assay and EMSA, the −1635 AP-1 motif on human CFH promoter was identified as the binding element for c-Jun and c-Fos. In a luciferase activity assay, mutation of the AP1 site eliminates Cd-induced increase of CFH promoter activity. Thus, the −1635 AP-1 motif on the CFH promoter region mediates Cd-inducible CFH gene expression.

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Section: Laser Capture Microdissectionmentioning

confidence: 99%

Cadmium Induces Glomerular Endothelial Cell–Specific Expression of Complement Factor H via the −1635 AP-1 Binding Site

Chen

Liu

et al. 2019

The Journal of Immunology

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“…However, a loss of HtrA4 failed to induce abnormalities in the morphology and function of the heart. The protein structure of HtrA4 is very similar to that of HtrA1, which is highly expressed in endothelial cells, smooth muscle cells and perivascular fibroblasts ( 22 ). In the vascular system, HtrA1 regulates transforming growth factor-β (TGF-β) signaling, and is involved in the pathogenesis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy ( 23 ).…”

Section: Discussionmentioning

confidence: 96%

Generation and characterization of mice with a conditional null allele of the HtrA4 gene

Liu

Hoh

2015

Molecular Medicine Reports

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High temperature requirement factor A4 (HtrA4) is a member of the HtrA family of serine peptidases involved in regulating protein-protein interactions. Little is known regarding the function of HtrA4 in humans and in mouse models. To gain insights into the role of HtrA4 in vivo, mice were generated with a conditional null allele of HtrA4 by flanking exons 4, 5 and 6 with loxP sites. Cre-mediated recombination, using a ubiquitously active Rosa26-Cre line, resulted in the deletion of the floxed region in the mouse genome. Mice homozygous for the recombinant allele (HtrA4−/−) were viable, fertile and appeared to be normal. The HtrA4 protein was detectable in coronary vessels and in the placenta. However, the loss of HtrA4 affected neither the basic heart nor placental functions. These mice, featuring a conditional null allele of HtrA4, may provide a valuable tool to investigate the role of HtrA4 in development and pathogenesis of coronary heart disease and preeclampsia.

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“…Due to the HTRA1 mutation, dysregulation of the inhibition of signaling by members of the TGF-β family induces cerebral small vessel disease and has also been linked to alopecia and spondylosis. The central pathology involves the lack of vascular smooth muscle cells (VSMCs) in the media and adventitial fibrosis, which invades the small penetrating arteries and mainly affects the cerebral white matter and basal ganglia ( 12 , 13 ). Loss of VSMCs is the primary feature of CARASIL, followed by deposition of granular materials in the media and fibrosis of the arterial wall, leading to ischemic and hemorrhagic consequences; consequently, diffuse white matter hyperintensity, lacunar infarctions, CMBs, and encephalatrophy are observed on MRI ( 14 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Diffuse Cerebral Microbleeds in Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Wen

Yuan

et al. 2022

Front. Neurol.

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Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary cerebral small vascular disease caused by a homozygous mutation in the high-temperature requirement A serine peptidase 1 (HTRA1) gene. Cerebral microbleeds (CMBs) are increasingly being recognized as neuroimaging findings occurring with cerebrovascular disease and have different etiologies. Mild to moderate CMBs are not unusual in CARASIL, and they are observed to affect cortical and subcortical structures; in contrast, diffuse CMBs, especially in the cerebellum, are rare. In this case, we report a novel mutation of HTRA1 in a 43-year-old woman whose imaging indicated multiple CMBs in all lobes, brain stem, and cerebellum. The amount and location of CMBs vary in CARASIL cases, and the potential cause is not fully understood. This study revealed that specific imaging findings of this patient may be related to a new genetic mutation.

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Loss of HtrA1-induced attenuation of TGF-β signaling in fibroblasts might not be the main mechanism of CARASIL pathogenesis

Cited by 7 publications

References 5 publications

Cadmium Induces Glomerular Endothelial Cell–Specific Expression of Complement Factor H via the −1635 AP-1 Binding Site

Cadmium Induces Glomerular Endothelial Cell–Specific Expression of Complement Factor H via the −1635 AP-1 Binding Site

Generation and characterization of mice with a conditional null allele of the HtrA4 gene

Case Report: Diffuse Cerebral Microbleeds in Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

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