Na+/H+ exchange in hypertension and in diabetes mellitus?facts and hypotheses

Abstract

An enhancement of Na⁺/H⁺ exchange (NHE) in blood cells of selected patients with essential hypertension and with diabetic nephropathy has been described by various investigators. Recent studies have shown that enhanced NHE activity persists in immortalized lymphoblasts from these patients after prolonged cell culture and, thus, appears to be under genetic control. Available evidence strongly argues against a mutation in the encoding gene or an overexpression of the NHE. Immortalized cells from hypertensive patients with enhanced NHE activity display two-fold enhanced agonistinduced rises of the cytosolic free Ca²⁺ concentration and the underlying reason was identified as an increased activation of pertussis toxin (PTX)-sensitive G proteins. The molecular mechanism(s) of this phenomenon have not yet been elucidated. It appears likely that similar changes contribute to the enhanced NHE activity phenotype in diabetic nephropathy, although experimental evidence for this is still lacking. An enhanced activation of PTX-sensitive G proteins could explain many of the hitherto unexplained phenomena in essential hypertension, e. g. inheritance, increased vasoconstriction, hypertrophy or remodeling of arterial blood vessels and the heart, enhanced platelet aggregation etc. In diabetes the same defect could provide the basis for the susceptibility to nephropathy, e.g. by enhancing the deleterious effects of autocrine and paracrine growth, factors. Thus, the experimental approach of immortalizing blood cells from patients with essential hypertension and diabetic nephropathy has opened new horizons in the identification of genetically fixed abnomalities in intracellular signal transduction which could contribute to both pathologies and which can now be studied without the confounding influences of the diabetic or hypertensivein vivo milieu.