S67 Dissecting Mechanisms in Endocrine Hypertension

Program: Symposia
Basic/Translational Session
Sunday, March 8, 2015: 11:15 AM-12:45 PM
Room 1 (San Diego Convention Center)
**This session is eligible for CME credit**

Chair:
William F Young Jr., MD, MSc, Mayo Clinic, Rochester, MN

Nothing to Disclose: WFY Jr.

This symposium gathers three important novelties in the field of endocrine hypertension: The first talk, by Professor Helmy Siragy, from University of Virginia, VA, is entitled "(Pro)Renin Receptor: Contributions and Potential For Therapy". (Pro)Renin receptor (PRR) is a newly discovered receptor. It is widely distributed in different organs. Recent studies identified some of its physiologic and pathologic contributions. It binds to prorenin and renin and enhances the conversion of angiotensinogen to angiotensin I, eventually leading to angiotensin II formation. However, PRR has functions independent of the renin-angiotensin system. Its main cellular signaling pathway is through ERK phosphorylation. Transgenic rats overexpressing PRR developed hypertension. It also implicated in development of preeclampsia. In addition, recent investigations link PRR to inflammation and development of diabetic nephropathy. The second talk, by Doctor Amanda Rickard, from the Prince Henry’s Institute, Clayton, Australia, is entitled: "Cell-Specific Mineralocorticoid Receptor Action in Hypertension". The renal hemodynamic consequence of excess mineralocorticoids ultimately leads to hypertension. Clinical and experimental evidence, however, highlights an important role for mineralocorticoid receptor (MR) signaling in the cardiovascular system in blood pressure regulation. The cardiovascular system is composed of an intricate arrangement of cells, many of which contain MR. While it is well accepted that inappropriate activation of MR in the cardiovascular system has pathophysiological consequences, the contribution of MR in each of the cell types for elevating blood pressure, driving tissue damage, recruiting and activating immune cells and promoting fibrosis has only recently been recognised. Dr Rickard’s laboratory and others have highlighted novel and distinct roles for MR signalling in the different cells types of the myocardium. MR in macrophages are essential for cardiac remodelling and blood pressure regulation in the mineralocorticoid/salt model, whereas MR in endothelial cells are necessary for macrophage recruitment but not blood pressure elevation. The presentation will discuss the current understanding of the cell-specific actions of MR signaling. The third talk, by Doctor Judith Favier, from INSERM Paris, is entitled: " SDH and Hypermethylation in Pheochromocytoma". Unexpected links between epigenetic and genetic alterations were recently identified with the demonstration that IDH mutations impair DNA demethylation in gliomas. Mutations affecting succinate dehydrogenase (SDH), another tricarboxylic acid cycle enzyme, have been identified in several cancers and are particularly frequent in paragangliomas. With a genome-wide analysis of DNA methylation changes in a large paraganglioma cohort, Dr Favier and collegues demonstrated that SDHx, and particularly SDHB-related metastatic tumors, display a hypermethylator phenotype, associated with down-regulation of key genes implicated in chromaffin cell differentiation. Succinate accumulation in SDH-deficient mouse chromaffin cells led to DNA hypermethylation by inhibition of 2-OG-dependent histone and DNA demethylases, and established a migratory phenotype reversed by decitabine treatment. These findings explain the oncogenic effect of SDH inactivation and the invasiveness of SDHB-mutated tumors and raise the possibility of innovative epigenetic therapies involving DNA demethylating agents for these cancers.

11:15 AM
Helmy M Siragy, M.D., Medicine, University of Virginia, Charlottesville, VA
Nothing to Disclose: HMS
11:45 AM
Amanda Jane Rickard, PhD, Centre for Endocrinology and Metabolic Diseases, MIMR-PHI Institute, Clayton, Australia
Nothing to Disclose: AJR
12:15 PM
Judith Favier, PhD, Paris-Cardiovascular Research Center (PARCC), Inserm, Paris, France
Nothing to Disclose: JF
See more of: Symposia