SALT-SENSITIVE HYPERTENSION IN A NEW RAT MODEL FOR PRIMARY GENERALIZED GLUCOCORTICOID RESISTANCE

Objectives: Glucocorticoids mainly act through the glucocorticoid receptor (GR) that functions as transcription factor. Primary generalized glucocorticoid resistance is characterized by generalized, partial target tissue resistance to glucocorticoids. Compensatory mechanisms lead to elevation in circulating adrenal steroids with mineralocorticoid and/or androgenic activity, and the clinical spectrum of this condition is broad ranging from asymptomatic to severe cases of hyperandrogenism and/or mineralocorticoid excess. So far, no animal model existed that mimics all clinical symptoms as observed in human generalized glucocorticoid resistance. Methods: We generated the first TALEN-engineered rats carrying knockout and in-frame mutations on the GR gene locus within its dimerization domain. Chronic administration of different salt diet to wildtype (WT) and heterozygous mutant GR rats (GR+/em2). Intra-arterial blood pressure (BP) was measured by Notocord acquisition system in conscious rats. Results: The GR+/em2 rats reproduced all clinical features of glucocorticoid resistance and show increased size of adrenal gland (adrenal hyperplasia), increase of corticosterone (hypercorticosteronism). These rats reproduce most of the clinical signs of primary generalized glucocorticoid resistance syndrome. Moreover, chronic administration of dietary salt induced a dose responses of increase in BP in both WT and GR+/em2 rats. The increase of BP in GR+/em2 rats was significantly higher compared to the WT group. Conclusion: We show that glucocorticoids induce salt-sensitive hypertension. This new rat model may be used for studying potassium, sodium, glucocorticoids/mineralocorticoids in the pathogenesis of hypertension and target organ damage. This work was supported by SNF-NCCR project.