High glucose stimulates aldosterone-induced hypertrophy via type I mineralocorticoid receptors in neonatal rat cardiomyocytes

Previous studies have shown that aldosterone plus salt loading cause cardiac hypertrophy in rats in vivo, and that in vitro, both aldosterone and glucose stimulate fibroblast growth. The present studies examined the effects of adrenal steroids via mineralocorticoid and glucocorticoid receptors (MR and GR) on [3H]leucine incorporation by neonatal rat cardiomyocytes in culture and the role of elevated glucose in modulating such effects. GR occupancy by corticosterone, the highly selective type II (glucocorticoid) receptor agonist RU28362, or high doses of aldosterone lowers incorporation; when this effect is blocked by coincubation with the glucocorticoid antagonist RU486, aldosterone, but not corticosterone, markedly elevates leucine incorporation, indicating a specific mineralocorticoid effect via MR. Incubation with high glucose alone does not increase incorporation, but markedly increases the hypertropic effect of aldosterone in terms of both threshold and maximum response. The glucose-aldosterone synergy is via MR and is completely blocked by spironolactone. The time course of increased incorporation is identical for aldosterone acting alone or with elevated glucose, consistent with widespread transcriptional effects and suggesting that the contribution of high glucose is not rate limiting. The glucose effect reflects neither induction of MR synthesis nor an increase in their affinity; it is specific, in that it is not mimicked by L-glucose or mannitol at equal concentrations, and is mediated via an increase in protein kinase C activity that can be measured in both soluble and particulate compartments. The role of this synergy in the cardiac sequelae of diabetes remains to be explored.