Immune system, salt, organ damage

The immune system, salt and hypertension-induced target organ damage

Our research is aimed at better understanding the role of innate and adaptive immunity in hypertension-induced organ damage. T cells, macrophages, and dendritic cells all harbor the AT1 receptor. Ang II stimulates T cell proliferation and dendritic cell migration. We showed that mice lacking the transcription factor Id2, a pivotal factor for Langerhans dendritic cells, are resistant to Ang II-induced hypertension and sequelae. We also observed that regulatory T cells modulate Ang II-induced cardiac damage to a point of therapeutic utility. Since our data suggested an interaction of the renin-angiotensin system, immune system and target organ damage (see scheme), we are investigating the role of angiotensin II in autoimmunity. In collaboration with Ralf Linker (Univ. Erlangen), we are now investigating whether blockade of the renin-angiotensin system improves non-cardiovascular autoimmunity. Our results suggest that by blocking the aspartyl protease renin, ACE and the AT1 receptor, autoimmune encephalitis in rodents can be effectively inhibited.

We are now extending our immunological studies to the investigation of inflammatory activation in the interstitium by hyperosmolarity through sodium. This line of investigation was initiated with Jens Titze (Univ. Erlangen/ Vanderbilt Univ.), with whom we have an intensive collaboration. With dietary sodium excess, sodium accumulates in the skin and activates the osmotic stress gene tonicity-responsive enhancer binding protein (TonEBP/NFAT5) in macrophages. TonEBP activity in macrophages results in secretion of VEGF-C promoting the clearance of hypertonic fluid from the interstitium. This circuit is critically dependent on macrophages and their ability to ward off hypertension in case of excess sodium supply. We have initiated a program to determine how hypertonicity induced by deranged sodium chloride storage affects the differentiation of T cells and macrophages. Finally, together with Thoralf Niendorf at the High-Field Magnetic Resonance facility (MDC), we are establishing technology to quantify skin and muscle Na+ concentration and content by 23Na-MRI. This will allow us to determine the tissue sodium (skin, muscle and bone marrow) in humans with hypertension, cardiovascular disease and patients with autoimmunity.