Fig. 2

Distinct mechanisms of lymphangiogenesis in certain kidney disease. a. In kidney hypertensive disease, sodium retention induces lymphangiogenesis through a Na +—TonEBP—VEGF-C pathway. Na + directly activates transcription factor of tonicity responsive enhancer-binding protein (TonEBP) in macrophages and dendritic cells (DCs) to promote expression of VEGF-C from macrophages, and then induces lymphangiogenesis. Sodium retention can directly activate DCs to express cytokines for further antigen-specific T cell accumulation and activation. Na + enters dendritic cells, subsequently leading to Ca2 + influx and then activation of protein kinase C, eventually resulting in increased expression of reactive oxygen species (ROS). ROS oxidates fatty acids into isolevuglandins (IsoLGs), which activates dendritic cells to produce proinflammatory cytokines (IL-1β, IL-6, IL-23) and activate T cells to proliferate and express inflammatory cytokines including TNF, IFN-γ and TGF-β. Lymphangiogenesis can reduce sodium retention, therefore inhibits DCs activation and the inflammatory response. b. In diabetic kidney disease, excessive cytokines expressed during the chronic inflammation condition create a specific microenvironment, which significantly induces abnormally-structured lymphangiogenesis