| dc.description.abstract | Hypertension is the leading contributor for all-cause mortality and morbidity worldwide and is a major risk factor for cardiovascular diseases, stroke, chronic kidney disease, and cognitive impairment. Renal immune cell infiltration and inflammation are well known to contribute to the pathogenesis of hypertension. The lymphatic system plays a crucial role in maintaining body fluid homeostasis and governs immune responses. However, the involvement of the renal lymphatic system in renal inflammation during hypertension is unknown. In the present study, we asked whether renal lymphatic vessels are altered during angiotensin II-induced hypertension. We hypothesized that renal lymphatic vessel density will be increased in angiotensin II-induced hypertension. To test our hypothesis, we investigated male and female mice with angiotensin II-induced hypertension. Results demonstrate that renal lymphatic vessel density is increased in male and female mice with angiotensin II-induced hypertension in association with renal inflammation. Our results also demonstrate that genetic augmentation of renal lymphatic vessel density reduces renal immune cell accumulation and prevents the development of angiotensin II-induced hypertension in male and female mice. Results from our in vitro studies demonstrate that angiotensin II activates immune cells to secrete lymphangiogenic and pro-inflammatory factors that exert proliferative and inflammatory effects on lymphatic endothelial cells. Using a nitric oxide inhibition-induced model of hypertension, we demonstrate that therapeutic augmentation of renal lymphatic expansion after hypertension is established attenuates blood pressure. Importantly, we demonstrate that this reduction in blood pressure was not associated with a reduction in renal immune cell accumulation, but was associated with increased natriuresis. A chronic high salt diet also induced an enhanced natriuretic response and lowered blood pressure in mice with augmented renal lymphatic vessel density. Our results thus establish a novel role for renal lymphatics in sodium homeostasis and blood pressure regulation during conditions of sodium retention such as hypertension and chronic high salt intake. Therapeutic renal lymphatic expansion also attenuated blood pressure in mice with angiotensin II-dependent and salt-sensitive hypertension. Thus, this study demonstrates the role of renal lymphatic vessels in blood pressure regulation and highlights the novel therapeutic potential of renal lymphatic vessels in controlling blood pressure during hypertension. | en |
