Enhancing Renal Lymphatic Expansion Prevents Hypertension in Mice.

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.

Renal inflammation and injury are associated with lymphangiogenesis in hypertension.

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.

Immune cell trafficking, lymphatics and hypertension.

Activated immune cell infiltration into organs contributes to the development and maintenance of hypertension. Studies targeting specific immune cell populations or reducing their inflammatory signalling have demonstrated a reduction in BP. Lymphatic vessels play a key role in immune cell trafficking and in resolving inflammation, but little is known about their role in hypertension. Studies from our laboratory and others suggest that inflammation-associated or induction of lymphangiogenesis is organ protective and anti-hypertensive. This review provides the basis for hypertension as a disease of chronic inflammation in various tissues and highlights how renal lymphangiogenesis is a novel regulator of kidney health and BP. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.

Recent Advances in Immunity and Hypertension.

Persistent immune system activation plays an important role in the development of various forms of hypertension. Activation of the innate immune system, inflammation, and subsequent adaptive immune system response causing end-organ injury and dysfunction ultimately leads to hypertension and its associated sequelae including coronary artery disease, heart failure, stroke, and chronic kidney disease. In this review, we will provide updates on the innate and adaptive immune cells involved in hypertension, the current understanding of how the immune system gets activated, and examine the recently discovered mechanisms involved in several forms of experimental hypertension.