Abstract 20064: DOCA-salt Hypertension Activates PlGF in the Spleen to Couple Sympathetic Drive and Immune System Activation

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Abstract

Introduction: A significant proportion of hypertensive patients is characterized by low-renin hypertension and salt-sensitivity. Deoxycorticosterone acetate (DOCA)-salt challenge resembles this condition in mice and its hypertensive effect has been also associated to overdrive of peripheral nervous system in organs typically targeted by high blood pressure, as kidneys and vasculature.

Hypothesis: Aim of this study was to explore whether DOCA-salt hypertension recruits immune system by overactivating sympathetic nervous system in lymphoid organs and whether this is relevant for blood pressure increase.

Methods and Results: The consolidated notion that hypertension induced by DOCA-salt challenge associated with T cells infiltration in the kidney similarly to Angiotensin II, raises a question about the possibility that the two hypertensive hits share also a common site of immune activation. In order to evaluate the role of the splenic immune system in DOCA-salt hypertension, we challenged splenectomized mice observing that they were unable to increase blood pressure. After, mice treated with DOCA-salt and subjected to coeliac ganglionectomy, interrupting the brain-to-spleen communication, did not activated sympathetic nervous system in the spleen. Then, we evaluated by immunofluorescence levels of the Placental Growth Factor (PlGF) that resulted significantly increased upon DOCA-salt in the marginal zone of the spleen. Furthermore, PlGF KO mice were significantly protected from the blood pressure increase caused by 21-days of DOCA-salt. In addition, absence of PlGF hampered DOCA-salt mediated T cells co-stimulation and their consequent deployment toward kidneys where they infiltrated tissue and provoked end-organ damage.

Conclusions: Overall our study demonstrates that DOCA-salt requires an intact sympathetic drive to the spleen for priming of immunity and consequent blood pressure increase. The coupling of nervous system and immune cells activation in the splenic marginal zone is established through a sympathetic-mediated PlGF release, suggesting that this pathway could be a valid therapeutic target in hypertensive conditions determined by different causes.

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