title: Recent topics on podocytes and aldosterone.
abstract: Podocyte injury is a major cause of proteinuria, a core component of chronic kidney disease. We reported that podocyte impairment underlied the early glomerulopathy in animal models of lifestyle-related diseases, such as hypertension and metabolic syndrome. Accumulating evidence suggests that overactivation of the aldosterone-mineralocorticoid receptor (MR) system has harmful effects on podocytes. We found that MR signaling was enhanced in such lifestyle-related diseases with podocyte injury and proteinuria, which were ameliorated by MR antagonist. Subsequent studies revealed that plasma aldosterone concentrations are not always increased in proteinuric conditions with renal MR activation, and the mechanisms of MR overactivation remained elusive. We recently identified a novel mechanism of Rac1-mediated podocyte impairment using RhoGDIα knockout mice; Rac1 potentiates the activity of MR in a ligand-independent manner, thereby accelerating podocyte injury. We demonstrated that the Rac1-MR pathway contributes to the ligand-independent aberrant MR activation in salt-sensitive hypertension and renal injury models. The importance of the RhoGDIα-Rac1-MR pathway in human glomerular disease is underscored by the findings that mutations in RhoGDIαgene cause nephrotic syndrome. Our results provide evidence that the Rac1-MR signal cascade as a novel therapeutic target for chronic kidney disease.
authors.affiliation: Department of Anatomy and Life Structure, School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan. Electronic address: minagase@juntendo.ac.jp.
authors.forename: Miki
authors.initials: M
authors.lastname: Nagase
mesh_terms: D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000378:metabolism; D024821:Metabolic Syndrome / Q000150:complications / Q000378:metabolism; D051379:Mice; D050199:Podocytes / Q000378:metabolism*; D011507:Proteinuria / Q000150:complications / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000450:Aldosterone