Cortisol and the renal handling of electrolytes: role in glucocorticoid-induced hypertension and bone disease

Abstract

Hypertension and osteoporosis are characteristic clinical features in patients with Cushing's syndrome or in those on glucocorticoid (GC) treatment. These two distinct complications of GC excess share one common denominator: an abnormal handling of cations, sodium (Na(+)) and calcium (Ca(2+)), either primarily or in part by the kidney tubule. The principal mechanism of GC-induced hypertension is overstimulation of the non-selective mineralocorticoid receptor (MR), resulting in renal Na(+) retention, volume expansion and finally to an increase in blood pressure. In mineralocorticoid target organs, such as the kidney, the MR is protected from GC occupation by the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), a gate-keeping enzyme, which converts cortisol to receptor-inactive cortisone. This enzyme allows aldosterone to be the physiological agonist of the MR despite significantly higher circulating levels of cortisol. Kinetic properties of 11betaHSD2 suggest that saturability of this enzyme can already be achieved at high-normal physiological plasma cortisol levels, thereby leading to ovestimualtion of the MR by cortisol in states of GC excess. The mechanisms of GC action on bone turnover are more complex. GCs increase bone resorption, inhibit bone formation and have an indirect action on bone by decreasing intestinal Ca(2+) absorption, but also inducing a sustained renal Ca(2+) excretion. The latter appears to be mediated through stimulation of the MR by GC. The prevention and treatment of GC-induced hypertension and osteoporosis include the use of the minimal effective dose of GC, some general measures, and the use of some specific drugs. Modulation of renal Na(+) and Ca(2+) excretion with some, but not all, diuretics represents an important specific (for hypertension) or supportive (for bone disease) therapeutic intervention.