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

• Published in: PloS one 2015-11, Vol.10 (11), p.e0143954-e0143954
• Main Authors: Montes-Cobos, Elena, Li, Xiao, Fischer, Henrike J, Sasse, André, Kügler, Sebastian, Didié, Michael, Toischer, Karl, Fassnacht, Martin, Dressel, Ralf, Reichardt, Holger M
• Format: Article
• Language: English
• Subjects: Aldosterone; Aldosterone - blood; Angiotensin; Animal tissues; Animals; Aorta; Cardiology; Cardiomyocytes; Care and treatment; Cloning; Collagen; Collagen - metabolism; Deactivation; Disease Models, Animal; Doxycycline; Echocardiography; Electrolytes - urine; Excretion; Fibrosis; Gene Expression; Gene Silencing; Genes; Heart; Heart diseases; Heart failure; Heart Failure - diagnosis; Heart Failure - etiology; Hypertension - complications; Hypertension - genetics; Hypertension - physiopathology; Hypertrophy; Immunology; Inactivation; Kidneys; Lethality; Ligands; Mice; Mice, Knockout; Mineralocorticoids; Physiology; Receptors, Mineralocorticoid - deficiency; Receptors, Mineralocorticoid - genetics; Renin; Renin - blood; Renin-angiotensin system; Renin-Angiotensin System - genetics; Risk factors; RNA, Small Interfering - genetics; RNA-mediated interference; Rodents; Smooth muscle; Sodium; Stem cells; Tightness; Transgenic animals; Transgenic mice
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0143954

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.