Role of human immune cells in resistant hypertension

• Applicant: Professor Dr. Johannes Stegbauer
• Subject Area: Nephrology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 449450873

Hypertension is the leading cause for cardiovascular mortality. A growing number of hypertensive patients has resistant hypertension (RHT). Patients with RHT have the highest risk for cardiovascular events. In RHT, blocking of the renin-angiotensin system, increasing sodium excretion by diuretics, or inducing vasodilation by calcium channel blockers fail to control blood pressure. A specific cause for RHT has not been identified, which seems necessary for better therapeutic strategies. Therefore, treatment of RHT is an unmet clinical need, since therapeutic options defined by pathophysiology are missing. Recent evidence suggests that adaptive immunity, in particular T cells, is the missing pathophysiological link leading to disturbances of blood pressure regulation involving blood vessels, kidney and sympathetic nervous system (SNS). Mice lacking B- and T cells are resistant to experimental hypertension. Selective transfer of T cells restores the ability to develop hypertension and endorgan damage. These effects are mediated by T cell derived proinflammatory cytokines in kidneys and vessels leading to vasoconstriction as well as salt and water reabsorption. Although the exact mechanism of T cell activation in hypertension is unknown, strong evidence for a tight interaction between T cells and the SNS exists. Recently, we showed that increased renal sympathetic norepinephrine release exaggerates hypertension and kidney injury in mice. In addition, increased sympathetic nerve activity (SNA) regulates homing of effector memory CD4 T cells and stimulates the release of proinflammatory cytokines from CD8 T cells. Reduction of SNA by renal nerve denervation (RDN) decreases renal T cell infiltration and lowers blood pressure in hypertensive mice. Based on these animal studies, we postulate that an activated SNS stimulates the adaptive immune system which then perpetuates hypertension and endorgan damage. In patients with RHT, SNA is significantly increased. Therefore, immune cell mediated endorgan damage may be clinically important in RHT. Several studies have shown that RDN reduces SNA, blood pressure and inflammation. We posit that severity of hypertension and endorgan damage is mediated by immune cell mediated mechanisms triggered by increased SNA. To test our hypothesis, we will perform a translational study. First, the inflammatory status and T cell signature of patients with RHT compared to healthy controls will be analyzed. Second, the role of human T cells in hypertension and end organ damage will be investigated by transferring T cells from RHT patients or healthy controls into a newly established humanized mouse model with angiotensin II induced experimental hypertension. With help of this unique approach, we hope to develop new concepts for the treatment of RHT.

• DFG Programme: Research Grants