LTBP4 affects renal fibrosis by influencing angiogenesis and altering mitochondrial structure
Journal
Cell death & disease
Journal Volume
12
Journal Issue
10
Date Issued
2021
Author(s)
Urban, Zsolt
Huang, Yue-Jhu
See, Daniel H W
Tsai, Yao-Chou
Abstract
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.
SDGs
Other Subjects
4 hydroxynonenal; alpha smooth muscle actin; angiopoietin 2; collagen type 1; endothelin 1; epidermal growth factor; fibronectin; gamma interferon; latent transforming growth factor beta binding protein 4; messenger RNA; mitofusin 2; regulator protein; unclassified drug; uvomorulin; vasculotropin; vasculotropin A; vasculotropin B; vasculotropin C; vasculotropin receptor; vasculotropin receptor 1; vimentin; latent transforming growth factor beta binding protein; LTBP4 protein, human; angiogenesis; animal experiment; animal model; animal tissue; Article; chronic kidney failure; controlled study; diabetic nephropathy; down regulation; genotype; glomerulonephritis; HEK293T cell line; HK-2 [Human kidney] cell line; human; human cell; human tissue; HUVEC cell line; immunohistochemistry; in vivo study; kidney biopsy; kidney fibrosis; mitochondrial respiration; mitochondrion; mouse; multiplex polymerase chain reaction; nonhuman; NRK-49F cell line; oxidative stress; oxygen consumption rate; protein expression; protein function; proximal tubule cell; real time polymerase chain reaction; real time reverse transcription polymerase chain reaction; respiratory function; RNA sequencing; transcriptomics; tubulogenesis; unilateral ureteral obstruction-induced renal fibrosis; upregulation; Western blotting; wild type; animal; biological model; C57BL mouse; cell differentiation; conditioned medium; fibrosis; gene expression profiling; HEK293 cell line; immunity; kidney; kidney tubule; knockout mouse; metabolism; mitochondrion; pathology; pharmacology; phenotype; ultrastructure; umbilical vein endothelial cell; ureter obstruction; Animals; Cell Differentiation; Culture Media, Conditioned; Fibrosis; Gene Expression Profiling; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Immunity; Kidney; Kidney Tubules; Latent TGF-beta Binding Proteins; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Models, Biological; Neovascularization, Physiologic; Phenotype; Ureteral Obstruction
Type
journal article