Abstract
Lymphatic vessels drain excess tissue fluids to maintain the interstitial environment. Lymphatic capillaries develop during the progression of tissue fibrosis in various clinical and pathological situations, such as chronic kidney disease, peritoneal injury during peritoneal dialysis, tissue inflammation, and tumor progression. The role of fibrosis-related lymphangiogenesis appears to vary based on organ specificity and etiology. Signaling via vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor (VEGFR)-3 is a central molecular mechanism for lymphangiogenesis. Transforming growth factor-β (TGF-β) is a key player in tissue fibrosis. TGF-β induces peritoneal fibrosis in association with peritoneal dialysis, and also induces peritoneal neoangiogenesis through interaction with VEGF-A. On the other hand, TGF-β has a direct inhibitory effect on lymphatic endothelial cell growth. We proposed a possible mechanism of the TGF-β–VEGF-C pathway in which TGF-β promotes VEGF-C production in tubular epithelial cells, macrophages, and mesothelial cells, leading to lymphangiogenesis in renal and peritoneal fibrosis. Connective tissue growth factor (CTGF) is also involved in fibrosis-associated renal lymphangiogenesis through interaction with VEGF-C, in part by mediating TGF-β signaling. Further clarification of the mechanism might lead to the development of new therapeutic strategies to treat fibrotic diseases.
Highlights
Lymphatic vessels reabsorb extravasated tissue fluid containing cells and proteins, and return them to the blood circulation, thereby maintaining interstitial homeostasis [1]
Signals mediated by vascular endothelial growth factor (VEGF)-C, VEGF-D, and its receptor VEGF receptor (VEGFR)-3 are recognized as a central molecular mechanism of lymphangiogenesis [6,7]
We recently reported that tubulointerstitial Connective tissue growth factor (CTGF) expression (CTGFti) at three months was an independent predictor of interstitial fibrosis (IF) and tubular atrophy (TA) at five years after transplantation in stable renal transplant recipients [129]
Summary
Lymphatic vessels reabsorb extravasated tissue fluid containing cells and proteins, and return them to the blood circulation, thereby maintaining interstitial homeostasis [1]. The increase of lymphatic capillaries, which is mainly induced by sprouting from basal lymphatics, is known as lymphangiogenesis, and is observed in a variety of diseases such as tumor metastasis [2], inflammation [3], wound healing [4], and organ transplantation [5]. Signals mediated by vascular endothelial growth factor (VEGF)-C, VEGF-D, and its receptor VEGF receptor (VEGFR)-3 are recognized as a central molecular mechanism of lymphangiogenesis [6,7]. Among various molecular mechanisms, transforming growth factor-β (TGF-β) plays a central role in tissue fibrosis [11]. Regarding the role of TGF-β in lymphangiogenesis, several studies showed that TGF-β has an inhibitory effect on the growth of lymphatic endothelial cells (LECs) [12,13,14]. Increased TGF-β levels promote VEGF-C production in specific cells and lead to lymphangiogenesis during tissue fibrosis
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