ABSTRACT
RATIONALE: Hypertension is associated with renal infiltration of activated immune cells; however, the role of renal lymphatics and immune cell exfiltration is unknown. OBJECTIVE: We tested the hypotheses that increased renal lymphatic density is associated with 2 different forms of hypertension in mice and that further augmenting renal lymphatic vessel expansion prevents hypertension by reducing renal immune cell accumulation. METHODS AND RESULTS: Mice with salt-sensitive hypertension or nitric oxide synthase inhibition-induced hypertension exhibited significant increases in renal lymphatic vessel density and immune cell infiltration associated with inflammation. Genetic induction of enhanced lymphangiogenesis only in the kidney, however, reduced renal immune cell accumulation and prevented hypertension. CONCLUSIONS: These data demonstrate that renal lymphatics play a key role in immune cell trafficking in the kidney and blood pressure regulation in hypertension.
Subject(s)
Hypertension/prevention & control , Kidney/immunology , Lymphangiogenesis , Lymphatic Vessels/physiopathology , Animals , Antigens, Differentiation/biosynthesis , Antigens, Differentiation/genetics , Calcium-Binding Proteins , Cell Movement , Homeodomain Proteins/biosynthesis , Homeodomain Proteins/genetics , Hypertension/chemically induced , Hypertension/physiopathology , Kidney/physiopathology , Lymphangiogenesis/genetics , Macrophages/immunology , Mice , Mice, Transgenic , NG-Nitroarginine Methyl Ester/toxicity , Nitric Oxide Synthase Type III/antagonists & inhibitors , Organ Specificity , Receptors, G-Protein-Coupled/metabolism , Sodium Chloride, Dietary/toxicity , T-Box Domain Proteins/biosynthesis , T-Box Domain Proteins/genetics , Th1 Cells/immunology , Tumor Suppressor Proteins/biosynthesis , Tumor Suppressor Proteins/genetics , Vascular Endothelial Growth Factor D/biosynthesis , Vascular Endothelial Growth Factor D/genetics , Vascular Endothelial Growth Factor Receptor-3/biosynthesis , Vascular Endothelial Growth Factor Receptor-3/geneticsABSTRACT
Lymphatic vessels are vital for the trafficking of immune cells from the interstitium to draining lymph nodes during inflammation. Hypertension is associated with renal infiltration of activated immune cells and inflammation; however, it is unknown how renal lymphatic vessels change in hypertension. We hypothesized that renal macrophage infiltration and inflammation would cause increased lymphatic vessel density in hypertensive rats. Spontaneously hypertensive rats (SHR) that exhibit hypertension and renal injury (SHR-A3 strain) had significantly increased renal lymphatic vessel density and macrophages at 40 wk of age compared with Wistar-Kyoto (WKY) controls. SHR rats that exhibit hypertension but minimal renal injury (SHR-B2 strain) had significantly less renal lymphatic vessel density compared with WKY rats. The signals for lymphangiogenesis, VEGF-C and its receptor VEGF-R3, and proinflammatory cytokine genes increased significantly in the kidneys of SHR-A3 rats but not in SHR-B2 rats. Fischer 344 rats exhibit normal blood pressure but develop renal injury as they age. Kidneys from 24-mo- and/or 20-mo-old Fischer rats had significantly increased lymphatic vessel density, macrophage infiltration, VEGF-C and VEGF-R3 expression, and proinflammatory cytokine gene expression compared with 4-mo-old controls. These data together demonstrate that renal immune cell infiltration and inflammation cause lymphangiogenesis in hypertension- and aging-associated renal injury.