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.
Highlights
Extensive lines of evidence implicate transforming growth factor beta (TGFβ) signalling in lung fibrosis, neoplasm, cardiomyopathy, diabetic nephropathy (DMN), and inflammation, correlating with disease severity in all cases [1]
LTBP4 expression is associated with tubular interstitial fibrosis (TIF) in mice and humans In ongoing efforts to understand the biological functions of LTBP4 in kidney fibrosis, we first measured Ltbp4 expression in the kidneys of mice subjected to ureteral obstruction (UUO) to elucidate the biological roles and molecular mechanisms of Ltbp4 in TIF
Using a UUO model in Ltbp4S−/− mice, we showed that LTBP4 protects against TIF in CKD via non-TGFβ-related signalling, enhancing angiogenesis and altering mitochondrial structure
Summary
Extensive lines of evidence implicate transforming growth factor beta (TGFβ) signalling in lung fibrosis, neoplasm, cardiomyopathy, diabetic nephropathy (DMN), and inflammation, correlating with disease severity in all cases [1]. Understanding the mechanisms of TGFβ activation and TGFβ-related signalling is relevant to developing therapeutic strategies for systemic diseases with major public health impacts. TGFβ acts ubiquitously as a cytokine, playing a crucial role in the synthesis of extracellular matrix (ECM) molecules, contributing to fibrotic disorders and regulating the immune system [2]. It influences cellular growth, differentiation, and proliferation at various stages of development and maintains tissue homeostasis during adulthood [3]. Latent TGFβ binding proteins (LTBPs) are a group of matrix proteins with important and complicated functions in the ECM. LTBPs represent potential regulators of fibrosis in different tissues
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