Background: Chronic kidney disease (CKD) counts acute kidney injuries (AKI) as one of its many underlying causes. Lymphatic vessels are important in modulating inflammation post-injury. Manipulating lymphatic vessel expansion thus has the potential to alter CKD progression. Previously, we demonstrated that renal lymphatic expansion prior to injury reduced CKD progression following an AKI. Here we test whether inducing lymphangiogenesis impacts established CKD.
Methods: Following CKD progression, kidney lymphatics were expanded by transgenic induction of kidney-specific overexpression of vascular endothelial growth factor-D (KidVD) in aristolochic acid (AA) nephropathy and cisplatin injury aggravated with chronic high phosphate diet (CisPi) models or by infusion of kidney-targeting nanoparticles (NP) loaded with the VEGFR-3 specific ligand VEGF-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, blood urea nitrogen, urinary protein creatinine ratio and urinary albumin creatinine ratio. Renal pro-inflammatory and fibrotic markers expression were measured by qRT-PCR.
Results: KidVD+ mice demonstrated expanded renal lymphatics while NP 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.
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http://dx.doi.org/10.34067/KID.0000000671 | DOI Listing |
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