title: Inducible Knock-Down of the Mineralocorticoid Receptor in Mice Disturbs Regulation of the Renin-Angiotensin-Aldosterone System and Attenuates Heart Failure Induced by Pressure Overload.
abstract: Mineralocorticoid receptor (MR) inactivation in mice results in early postnatal lethality. Therefore we generated mice in which MR expression can be silenced during adulthood by administration of doxycycline (Dox). Using a lentiviral approach, we obtained two lines of transgenic mice harboring a construct that allows for regulatable MR inactivation by RNAi and concomitant expression of eGFP. MR mRNA levels in heart and kidney of inducible MR knock-down mice were unaltered in the absence of Dox, confirming the tightness of the system. In contrast, two weeks after Dox administration MR expression was significantly diminished in a variety of tissues. In the kidney, this resulted in lower mRNA levels of selected target genes, which was accompanied by strongly increased serum aldosterone and plasma renin levels as well as by elevated sodium excretion. In the healthy heart, gene expression and the amount of collagen were unchanged despite MR levels being significantly reduced. After transverse aortic constriction, however, cardiac hypertrophy and progressive heart failure were attenuated by MR silencing, fibrosis was unaffected and mRNA levels of a subset of genes reduced. Taken together, we believe that this mouse model is a useful tool to investigate the role of the MR in pathophysiological processes.
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Montes-Cobos
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany.
authors.forename: Henrike J
authors.initials: HJ
authors.lastname: Fischer
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Sasse
authors.affiliation: Department of Neurology, Center for Molecular Physiology of the Brain, University Medical Center Göttingen, 37073 Göttingen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kügler
authors.affiliation: Institute of Pharmacology, University Medical Center Göttingen, 37073 Göttingen, Germany.|Department of Cardiology and Pneumology, University Medical Center Göttingen, 37073 Göttingen, Germany.|Partner site Göttingen, German Center for Cardiovascular Research (DZHK), 37073 Göttingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Didié
authors.affiliation: Department of Cardiology and Pneumology, University Medical Center Göttingen, 37073 Göttingen, Germany.|Partner site Göttingen, German Center for Cardiovascular Research (DZHK), 37073 Göttingen, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Toischer
authors.affiliation: Endocrine and Diabetes Unit, Department of Internal Medicine I, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany.|Partner site Göttingen, German Center for Cardiovascular Research (DZHK), 37073 Göttingen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Dressel
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany.
authors.forename: Holger M
authors.initials: HM
authors.lastname: Reichardt
mesh_terms: D000450:Aldosterone / Q000097:blood; D000818:Animals; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D004573:Electrolytes / Q000652:urine; D005355:Fibrosis; D015870:Gene Expression; D020868:Gene Silencing; D006333:Heart Failure / Q000175:diagnosis / Q000209:etiology*; D006973:Hypertension / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000172:deficiency / Q000235:genetics*; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000235:genetics*
chemical_list: D004573:Electrolytes; D034741:RNA, Small Interfering; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D003094:Collagen; D012083:Renin