Distinct sites of renal fibrosis in Crim1 mutant mice arise from multiple cellular origins
| Autor: | Yu Leng, Phua, Nick, Martel, David J, Pennisi, Melissa H, Little, Lorine, Wilkinson |
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| Rok vydání: | 2012 |
| Předmět: |
Genetic Markers
Epithelial-Mesenchymal Transition Genotype Mice Transgenic Kidney Monocytes Mice Animals Cell Lineage Gene Regulatory Networks RNA Messenger Myofibroblasts Integrases Gene Expression Profiling Endothelial Cells Receptor Protein-Tyrosine Kinases Bone Morphogenetic Protein Receptors Fibrosis Receptor TIE-2 Platelet Endothelial Cell Adhesion Molecule-1 Luminescent Proteins Phenotype Gene Expression Regulation Mutation Kidney Diseases Biomarkers |
| Zdroj: | The Journal of pathology. 229(5) |
| ISSN: | 1096-9896 |
| Popis: | Crim1 is a transmembrane protein that regulates the bioavailability of growth factors such as VEGFA. Crim1(KST264)(/)(KST264) hypomorphic mice develop renal disease characterized by glomerular cysts and loss of endothelial integrity, progressing to peritubular and pericystic fibrosis. Peritubular capillary endothelial cells display morphological changes as well as detachment from the basement membrane. In this study, gene expression profiling of CD31(+) endothelial cells isolated from Crim1(KST264)(/)(KST264) kidneys showed up-regulation of transcripts associated with fibrosis (Col3a1, Loxl1), endothelial dysfunction (Abp1, Dcn, Lcn2), biomarkers of renal damage (Lcn2, Havcr1/Kim1) as well as evidence for a TGFβ1/TNF-associated inflammatory process. To determine whether the aberrant endothelium may in part contribute to the fibrogenic process, Tie2Cre-DsRed lineage tracing was undertaken in Crim1(KST264/KST264) mice. Approximately 31% of de novo αSMA(+) myofibroblasts detected within the tubulointerstitium were Tie2(+) DsRed(+) . However, 5.3% were F4/80(+) DsRed(+) , indicating a small population of myofibroblasts of monocytic rather than endothelial origin. In contrast, only 12% of myofibroblasts located around glomerular cysts were Tie2(+) DsRed(+) , with 7.7% being monocyte-derived (F4/80(+) DsRed(+) ). Collectively, this model supports the involvement of endothelial cells/monocytes in fibrosis within the tubulointerstitium, but also the heterogeneity of the fibrotic process even within distinct regions of the same kidney. |
| Databáze: | OpenAIRE |
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