The Department of Biomedicine

BBB Seminar: Jens Titze

Extrarenal regulation of volume and blood pressure homeostasis

Jens Titze
Department of Nephrology and Hypertension, Friedrich-Alexander University, Erlangen-Nürnberg, Germany

Internal environment regulation, particularly volume and osmoregulation, has been a fundamental concept important to physiologists and clinicians for almost two centuries. Na+ balance, intracellular K+ homeostasis, the crucial role of the Na+,K+-ATPase pump, osmotic forces, and the overriding effect of the kidney on maintaining homeostasis are notions that have been taught by many and accepted by most for over 50 years. Nevertheless, contradictory findings, problems with simplistic balance explanations, and the notion of salt-sensitive and salt-resistant hypertension have been nagging headaches in the straightforward, two-compartment model of electrolyte balance.

Recent findings suggest that Na+ can be accumulated without commensurate water retention in the interstitium of the skin, and this skin Na+ storage is paralleled by increased polymerization and sulfation of glycosaminoglycans in the Na+ reservoir. Subcutaneous tissue macrophages express the transcription factor tonicity enhancer binding protein (TonEBP) in response to osmotic stress which is induced by Na+ storage in the interstitium. The macrophages thereby secrete VEGF-C, which binds to VEGF-R3 of lymphendothelial cells and thereby induces hyperplasia of the lymphcapillary network. Furthermore, VEGF-C, which also binds to VEGF-R2, leads to increased expression of endothelial NO synthase (eNOS) in blood capillaries. These findings suggest that interstitial Na+ and volume homeostasis indeed relies on local, independent regulatory mechanisms. Tissue Na+ excess is detected within macrophages that act as moblile osmo-sensors. Besides Na+ sensing, the immune cells increase via TonEBP binding to the VEGF-C promoter not only the size of the lymphatic network and its capacity to transport interstitial Na+ and fluid, but also the capacity to synthesize NO in small blood vessels. Blockade of the macrophage driven VEGF-C response not only deteriorates two different forms of salt-sensitive hypertension in the rat, but also resulted in a conversion from a salt-resistant blood pressure phenotype into a salt-sensitive phenotype.

These findings do not abrogate the notion of pressure natriuresis and renal regulatory function. However, we do suggest that extracellular Na+, volume and blood pressure homeostasis cannot be maintained without extrarenal regulatory mechanisms.

Host: Helge Wiig, Department of Biomedicine