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Geza Fejes-Toth, DMD

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Professional Interests

The classical targets cells of aldosterone (Aldo) reside in the kidney and colon. However, mineralocorticoid receptors (MRs) are also expressed in non-epithelial tissues including the brain, heart and vasculature, but the role of these MRs in cardiovascular function remains largely unexplored. The MR has equal affinity for Aldo and the glucocorticoids cortisol/corticosterone (Cort). While in epithelial tissues Cort is degraded thereby allowing Aldo to occupy the MR, in non-epithelial tissues Cort metabolism is low, and thus both Aldo and Cort can bind the MR. Interestingly, there is increasing evidence that the two hormones can initiate distinct, even opposing effects through the MR.

Recent clinical studies demonstrated a remarkable improvement in mortality and morbidity of patients with chronic heart failure (CHF) when MR blockers (MRBs) are introduced in addition to standard care. MRBs also reduce end-organ damage resulting from inappropriate Aldo-to-volume status, and ameliorate atherosclerotic vascular lesions. However, the organ systems that mediate these beneficial effects, the ligand(s) displaced by MRBs and the underlying molecular mechanisms remain poorly understood. Our hypothesis is that the physiological role of non-epithelial MRs is to guard against cardiovascular collapse during severe volume depletion but their activation becomes maladaptive in a setting of volume expansion. We also hypothesize that in severe volume depletion and in CHF the MR is converted from a Cort- to an Aldo-bound state, and the cardiovascular maladaptations are brought about by this ligand switch. The overall goals of this project are to localize the MR-mediated cardiovascular effects of corticosteroids in health and disease, to determine which hormone mediates these effects, and to understand the underlying cellular and molecular mechanisms. A better understanding of the role of cardiovascular MRs and the cellular and molecular mechanisms that adrenal steroids initiate via these receptors could pave the way toward the development of more effective new drugs with fewer adverse effects for the treatment of cardiovascular disease.

Grant Information

NIH RO1

Courses Taught

PEMM 101, Medical Physiology