title: Mineralocorticoid receptor as a therapeutic target in chronic kidney disease and hypertension.
abstract: The kidney has a central role in long-term control of blood pressure, and decreased kidney function is a common but difficult-to-treat cause of hypertension. Conversely, elevated blood pressure contributes to the progression of chronic kidney disease. Steroid hormone aldosterone and its receptor mineralocorticoid receptor (MR) contribute to hypertension by increasing renal salt reabsorption and promote kidney dysfunction through direct effects on renal parenchymal cells. Accumulating data indicate that various mechanisms affect aldosterone-MR signaling. Using a genetically engineered mouse model, we identified crosstalk between small GTPase Rac1 and MR. This crosstalk pathway promotes glomerular podocyte injury, and is also involved in the pathogenesis of hypertension. Notably, salt loading increases renal Rac1 activity in several models of salt-sensitive hypertension, which, in the presence of aldosterone, synergistically activates MR signaling, causing hypertension and kidney injury. There is also a mechanism regulating MR in a cell-selective manner. In the principal cells of the collecting duct, aldosterone directly binds and activate MR. In neighboring intercalated cells, however, binding of aldosterone to MR is regulated by phosphorylation at the ligand-binding domain. This mechanism serves as a switch to turn on electrolyte flux pathways in intercalated cells, allowing aldosterone to exert distinct effects in different physiological contexts. Given the potential benefit of MR blockade in hypertensive kidney disease, the delineation of these pathways may lead to the identification of alternative therapeutic targets. In this review, we discuss the roles of MR in mediating kidney disease and hypertension, with a focus on the crosstalk among related signaling pathways.
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Teikyo University School of Medicine, Tokyo, Japan.|Division of Clinical Epigenetics, Research center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Shibata
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Teikyo University School of Medicine, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ishizawa
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Teikyo University School of Medicine, Tokyo, Japan.
authors.forename: Shunya
authors.initials: S
authors.lastname: Uchida
mesh_terms: D000818:Animals; D006801:Humans; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D018161:Receptors, Mineralocorticoid