The human mineralocorticoid receptor (MR) serves as the final effector of the renin-angiotensin-aldosterone pathway and is a key regulator of sodium homeostasis in the distal nephron. These investigators recently described a novel form of human Mendelian hypertension caused by a gain of function mutation novel form of human Mendelian hypertension caused by grain of function mutation in MR. The mutation results in constitutive activity of the receptor and alters receptor specificity such that progesterone, normally an MR antagonist, functions as an agonist. Consistent with the dramatic rise in progesterone levels in pregnancy, carriers of this mutation develop severe pregnancy-related hypertension. Previous studies indicate that bending of helix 3, and that this mutant achieves the 21-0H independent bending of helix 3 via creation of a novel van der Waals interaction between helix 3 and helix 5. The observations that this helix 3- helix-5 interaction is highly conserved among diverse nuclear receptors indicated its general role in receptor activation. In this grant, we propose both biochemical and clinical studies to augment our understanding of MR function in human physiology and hypertension. They will assess the proposed model for MR activation and identify specific residues necessary for MR specificity and activity. Furthermore, they will identify nuclear co-regulators required for MR activity and identify the biochemical requirements for MR activation. Clinically, they propose to determine the prevalence of disease causing MR mutations in a variety of clinical situations and finally, determine extra-renal effects of an activated MR in patients carrying this mutation.
| Zhang, Junhui; Geller, David S (2008) Helix 3-helix 5 interactions in steroid hormone receptor function. J Steroid Biochem Mol Biol 109:279-85 |
| Mani, Arya; Radhakrishnan, Jayaram; Wang, He et al. (2007) LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315:1278-82 |
| Alvarez de la Rosa, Diego; Gimenez, Ignacio; Forbush, Biff et al. (2006) SGK1 activates Na+-K+-ATPase in amphibian renal epithelial cells. Am J Physiol Cell Physiol 290:C492-8 |
| Zhang, Junhui; Tsai, Francis T F; Geller, David S (2006) Differential interaction of RU486 with the progesterone and glucocorticoid receptors. J Mol Endocrinol 37:163-73 |
| Zhang, Junhui; Simisky, Jessica; Tsai, Francis T F et al. (2005) A critical role of helix 3-helix 5 interaction in steroid hormone receptor function. Proc Natl Acad Sci U S A 102:2707-12 |
| Geller, David S (2005) Mineralocorticoid resistance. Clin Endocrinol (Oxf) 62:513-20 |
| Wilson, Frederick H; Hariri, Ali; Farhi, Anita et al. (2004) A cluster of metabolic defects caused by mutation in a mitochondrial tRNA. Science 306:1190-4 |
| Coric, Tatjana; Hernandez, Nelmary; Alvarez de la Rosa, Diego et al. (2004) Expression of ENaC and serum- and glucocorticoid-induced kinase 1 in the rat intestinal epithelium. Am J Physiol Gastrointest Liver Physiol 286:G663-70 |
| Geller, David S (2004) A genetic predisposition to hypertension? Hypertension 44:27-8 |
| Francis, Jean; Zhang, Junhui; Farhi, Anita et al. (2004) A novel SGLT2 mutation in a patient with autosomal recessive renal glucosuria. Nephrol Dial Transplant 19:2893-5 |
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