Therapeutically Induced Lymphangiogenesis Is Ineffective in Resolving Established Kidney Disease in Mice.

KEY POINTS: CKD is a state of unresolved kidney inflammation. Lymphatic vessels and lymphangiogenesis regulate inflammation, and thus, more lymphatics could potentially resolve inflammation and CKD progression. Induction of kidney-specific lymphangiogenesis in three mouse CKD models did not improve kidney function and has the potential to worsen CKD. BACKGROUND: CKD counts AKI as one of its many underlying causes. Lymphatic vessels are important in modulating inflammation postinjury. Manipulating lymphatic vessel expansion thus has the potential to alter CKD progression. Previously, we demonstrated that renal lymphatic expansion before injury reduced CKD progression after an AKI. Here, we test whether inducing lymphangiogenesis affects established CKD. METHODS: After CKD progression, kidney lymphatics were expanded by transgenic induction of kidney-specific overexpression of vascular endothelial growth factor-D in aristolochic acid (AA) nephropathy and cisplatin injury aggravated with chronic high phosphate diet (CisPi) models or by infusion of kidney-targeting nanoparticles loaded with the vascular endothelial growth factor receptor-3 specific ligand vascular endothelial growth factor-C C156S in a progressive proteinuria (POD) model. Renal fibrosis and lymphatic density were determined by picrosirius red staining and immunofluorescence, respectively. Renal function was assessed by creatinine clearance rate, serum creatinine, BUN, and urinary albumin-creatinine ratio. Renal proinflammatory and fibrotic markers expression were measured by quantitative RT-PCR. RESULTS: Kidney-specific overexpression of vascular endothelial growth factor-D+ mice demonstrated expanded renal lymphatics, while nanoparticles treatment minimally expanded lymphatics. In neither the AA nor POD model did lymphangiogenesis improve renal function or fibrosis. AA mice showed decreased Tgfb1 expression and POD mice showed increased Col4a1 expression. Expansion worsened function in CisPi CKD and increased fibrosis. CisPi kidneys also demonstrated increased expression of Mcp-1, Il1b, Col1a1, and Tgfb1 and increased macrophage numbers. CONCLUSIONS: Therapeutically induced lymphatic expansion is ineffective in resolving established CKD and has the potential to further worsen CKD progression.