Augmenting Renal Lymphatic Density Prevents Angiotensin II-Induced Hypertension in Male and Female Mice

• Published in: American journal of hypertension 2020-01, Vol.33 (1), p.61-69
• Main Authors: Balasubbramanian, Dakshnapriya, Gelston, Catalina A Lopez, Lopez, Alexandra H, Iskander, Geina, Tate, Winter, Holderness, Haley, Rutkowski, Joseph M, Mitchell, Brett M
• Format: Article
• Language: English
• Subjects: Angiotensin II; Animals; Blood Pressure; Cells, Cultured; Disease Models, Animal; Editor's Choice; Endothelial Cells - metabolism; Female; Hypertension - chemically induced; Hypertension - metabolism; Hypertension - physiopathology; Hypertension - prevention & control; Kidney - metabolism; Kidney - physiopathology; Lymphangiogenesis; Lymphatic Vessels - metabolism; Lymphatic Vessels - physiopathology; Macrophages, Peritoneal - metabolism; Male; Mice, Inbred C57BL; Mice, Transgenic; Original Contributions; Spleen - metabolism; Vascular Endothelial Growth Factor D - genetics; Vascular Endothelial Growth Factor D - metabolism
• ISSN: 0895-7061; 1941-7225
• DOI: 10.1093/ajh/hpz139

Abstract BACKGROUND Renal inflammation and immune cell infiltration are characteristic of several forms of hypertension. Our laboratory has previously demonstrated that renal-inflammation-associated lymphangiogenesis occurs in salt-sensitive and nitric-oxide-inhibition-induced hypertension. Moreover, enhancing renal lymphatic density prevented the development of these two forms of hypertension. Here, we investigated the effects of angiotensin II-induced hypertension on renal lymphatic vessel density in male and female mice. METHODS Wild-type and genetically engineered male and female mice were infused with angiotensin II for 2 or 3 weeks. Isolated splenocytes and peritoneal macrophages from mice, and commercially available mouse lymphatic endothelial cells were used for in vitro studies. RESULTS Compared to vehicle controls, angiotensin II-infused male and female mice had significantly increased renal lymphatic vessel density in association with pro-inflammatory immune cells in the kidneys of these mice. Direct treatment of lymphatic endothelial cells with angiotensin II had no effect as they lack angiotensin II receptors; however, angiotensin II treatment of splenocytes and peritoneal macrophages induced secretion of the lymphangiogenic growth factor VEGF-C in vitro. Utilizing our genetic mouse model of inducible renal lymphangiogenesis, we demonstrated that greatly augmenting renal lymphatic density prior to angiotensin II infusion prevented the development of hypertension in male and female mice and this was associated with a reduction in renal CD11c+F4/80- monocytes. CONCLUSION Renal lymphatics play a significant role in renal immune cell trafficking and blood pressure regulation, and represent a novel avenue of therapy for hypertension.