Distinct sites of renal fibrosis in Crim1 mutant mice arise from multiple cellular origins

Crim1 is a transmembrane protein that regulates the bioavailability of growth factors such as VEGFA. Crim1KST264/KST264 hypomorphic mice develop renal disease characterized by glomerular cysts and loss of endothelial integrity, progressing to peritubular and pericystic fibrosis. Peritubular capillar...

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Bibliographic Details
Published in:The Journal of pathology 2013-04, Vol.229 (5), p.685-696
Main Authors: Phua, Yu Leng, Martel, Nick, Pennisi, David J, Little, Melissa H, Wilkinson, Lorine
Format: Article
Language:English
Subjects:
Animals
Biomarkers - metabolism
Bone Morphogenetic Protein Receptors - genetics
Bone Morphogenetic Protein Receptors - metabolism
Cell Lineage - genetics
collagen type III
Crim1
endothelial cells
Endothelial Cells - metabolism
Endothelial Cells - pathology
endothelial-mesenchymal transition
Epithelial-Mesenchymal Transition
Fibrosis
Gene Expression Profiling
Gene Expression Regulation
Gene Regulatory Networks
Genetic Markers
Genotype
glomerulus
Havcr1/Kim1
Integrases - genetics
Kidney - blood supply
Kidney - metabolism
Kidney - pathology
Kidney Diseases - genetics
Kidney Diseases - metabolism
Kidney Diseases - pathology
Luminescent Proteins - genetics
Luminescent Proteins - metabolism
Mice
Mice, Transgenic
monocytes
Monocytes - metabolism
Monocytes - pathology
Mutation
Myofibroblasts - metabolism
Myofibroblasts - pathology
Phenotype
Platelet Endothelial Cell Adhesion Molecule-1 - metabolism
Receptor Protein-Tyrosine Kinases - genetics
Receptor, TIE-2
renal fibrosis
renal inflammation
RNA, Messenger - metabolism
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Summary:Crim1 is a transmembrane protein that regulates the bioavailability of growth factors such as VEGFA. Crim1KST264/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 Crim1KST264/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 Crim1KST264/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. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
ISSN:0022-3417
1096-9896
DOI:10.1002/path.4155