Transforming growth factor-β induces vascular endothelial growth factor-C expression leading to lymphangiogenesis in rat unilateral ureteral obstruction

Abstract

Inflammation is recognized as an important contributor to lymphangiogenesis; however, in tubulointerstitial lesions in human chronic kidney diseases, this process is better correlated with the presence of myofibroblasts rather than macrophages. As little is known about the interaction between lymphangiogenesis and renal fibrosis, we utilized the rat unilateral ureteral obstruction model to analyze inflammation, fibrosis, lymphangiogenesis, and growth factor expression. Additionally, we determined the relationship between vascular endothelial growth factor-C (VEGF-C), an inducer of lymphangiogenesis, and the profibrotic factor, transforming growth factor-β1 (TGF-β1). The expression of both TGF-β1 and VEGF-C was detected in tubular epithelial and mononuclear cells, and gradually increased, peaking 14 days after ureteral obstruction. The kinetics and localization of VEGF-C were similar to those of TGF-β1, and the expression of these growth factors and lymphangiogenesis were linked with the progression of fibrosis. VEGF-C expression was upregulated by TGF-β1 in cultured proximal tubular epithelial cells, collecting duct cells, and macrophages. Both in vitro and in vivo, the induction of VEGF-C along with the overall appearance of lymphatics in vivo was specifically suppressed by the TGF-β type I receptor inhibitor LY364947. Thus, TGF-β1 induces VEGF-C expression, which leads to lymphangiogenesis.

Therapeutic effects of DZ2002, a reversible SAHH inhibitor, on lupus-prone NZB×NZW F1 mice via interference with TLR-mediated APC response

“…DZ2002 treatment significantly decreased the serum levels of IL-17A and IL-23p19, and IL-12p40 was slightly affected ( Figure 2B). In addition to its role as a differentiation factor, up-regulated TGF-β has an alternative function in glomerular injury, accelerating nephritis by facilitating excessive matrix deposition [31][32][33] . The reduced serum level of TGF-β might partially contribute to the protective function of DZ2002 against renal injury.…”

Vascular endothelial growth factor receptor-3 is a novel target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury

“…[5][6][7]23,24 The antibodies used are listed in Supplementary Table 1. Mast cells were evaluated using sections stained with 0.2% toluidine blue.…”

“…18S ribosomal RNA was used as an endogenous control. 5,7,23,24 Assessment of Lymphatic Absorption To assess absorption via the lymphatic vessels, animals that received 2000 μl of 7.5% icodextrin peritoneal dialysis solution into the peritoneal cavity were killed at 4 h after infusion. An accurate drained volume was measured.…”

“…RNA preparation and the synthesis of first-strand cDNA were performed as described previously. [5][6][7]23,24 Total RNA (1 μg) was then reverse transcribed. Quantitative real-time PCR (qPCR) analysis was performed with an Applied Biosystems (South San Francisco, CA, USA) Prism 7500HT sequence detection system using TaqMan gene expression assays as described previously.…”

“…5 Thus, we proposed that lymphangiogenesis in the peritoneal membrane, similar to renal fibrosis is linked with the fibrotic process via the TGF-β-VEGF-C pathway. [6][7][8] The lymphatic absorption rate, which is measured by the rate at which intraperitoneally administered radioactive serum albumin or the macromolecule dextran 70 disappears, is significantly higher in patients with ultrafiltration failure, and lymphatic absorption is considered to be one of the causes of the decrease in net ultrafiltration. [9][10][11][12] However, the results from these clinical approaches have been controversial, 13,14 and there are no other methods available to assess lymphatic function.…”