LTBP4 affects renal fibrosis by influencing angiogenesis and altering mitochondrial structure
| Autor: | Yao-Chou Tsai, Daniel H. W. See, Yue-Jhu Huang, Tzu-Ming Jao, Zsolt Urban, Wei-Chou Lin, Chi-Ting Su, Jenq-Wen Huang |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Angiogenesis Immunology Neovascularization Physiologic Pathogenesis Kidney Models Biological Article Cellular and Molecular Neuroscience chemistry.chemical_compound Renal fibrosis Human Umbilical Vein Endothelial Cells Animals Humans Tube formation Mice Knockout biology QH573-671 Gene Expression Profiling Immunity Cell Differentiation Cell Biology Transforming growth factor beta Fibrosis Mitochondria Vascular endothelial growth factor Mice Inbred C57BL Vascular endothelial growth factor A Transforming growth factor beta binding HEK293 Cells Kidney Tubules Phenotype chemistry Latent TGF-beta Binding Proteins Culture Media Conditioned Cancer research biology.protein Human umbilical vein endothelial cell Cytology Ureteral Obstruction Cell signalling |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 12, Iss 10, Pp 1-11 (2021) |
| ISSN: | 2041-4889 |
| Popis: | Transforming growth factor beta (TGFβ) signalling regulates extracellular matrix accumulation known to be essential for the pathogenesis of renal fibrosis; latent transforming growth factor beta binding protein 4 (LTBP4) is an important regulator of TGFβ activity. To date, the regulation of LTBP4 in renal fibrosis remains unknown. Herein, we report that LTBP4 is upregulated in patients with chronic kidney disease and fibrotic mice kidneys created by unilateral ureteral obstruction (UUO). Mice lacking the short LTBP4 isoform (Ltbp4S−/−) exhibited aggravated tubular interstitial fibrosis (TIF) after UUO, indicating that LTBP4 potentially protects against TIF. Transcriptomic analysis of human proximal tubule cells overexpressing LTBP4 revealed that LTBP4 influences angiogenic pathways; moreover, these cells preserved better mitochondrial respiratory functions and expressed higher vascular endothelial growth factor A (VEGFA) compared to wild-type cells under hypoxia. Results of the tube formation assay revealed that additional LTBP4 in human umbilical vein endothelial cell supernatant stimulates angiogenesis with upregulated vascular endothelial growth factor receptors (VEGFRs). In vivo, aberrant angiogenesis, abnormal mitochondrial morphology and enhanced oxidative stress were observed in Ltbp4S−/− mice after UUO. These results reveal novel molecular functions of LTBP4 stimulating angiogenesis and potentially impacting mitochondrial structure and function. Collectively, our findings indicate that LTBP4 protects against disease progression and may be of therapeutic use in renal fibrosis. |
| Databáze: | OpenAIRE |
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