Silencing of the Mineralocorticoid Receptor by Ribonucleic Acid Interference in Transgenic Rats Disrupts Endocrine Homeostasis

Author:

Lim Hee-Young1,van den Brandt Jens2,Fassnacht Martin3,Allolio Bruno3,Herold Marco J.1,Reichardt Holger M.2

Affiliation:

1. University of Würzburg (H.-Y.L., M.J.H., H.M.R.), Institute for Virology and Immunobiology, 97078 Würzburg, Germany

2. University of Göttingen (J.v.d.B., H.M.R.), Medical School, Department of Cellular and Molecular Immunology, 37073 Göttingen, Germany

3. University of Würzburg (M.F., B.A.), Department of Internal Medicine I, Endocrine and Diabetes Unit, 97080 Würzburg, Germany

Abstract

Abstract Currently, gene disruption by homologous recombination in embryonic stem cells is only feasible in mice. To circumvent this problem, we silenced mineralocorticoid receptor (MR) expression by RNA interference in knockdown rats generated through lentiviral transgenesis. Analysis of the F1 progeny at 3 wk of age revealed strongly decreased MR levels. This was specific for the targeted gene and related to the abundance of the short interfering RNA. Reminiscent of MR knockout mice, the transgenic rats showed a reduced body weight, elevated serum aldosterone levels, increased plasma renin activity, and altered expression of MR target genes. Some of these effects correlated with the degree to which MR mRNA expression was reduced. Whereas disruption of the MR by gene targeting in mice leads to postnatal death, our strategy also allowed obtaining adult knockdown rats with defects in hormone and electrolyte homeostasis resembling pseudohypoaldosteronism. In conclusion, this is the first example of a human disease model based on RNA interference in rats.

Publisher

The Endocrine Society

Subject

Endocrinology,Molecular Biology,General Medicine

Cited by 13 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Mineralocorticoid Resistance;Endocrinology;2023

2. Mineralocorticoid Resistance;Endocrinology;2023

3. The invention of aldosterone, how the past resurfaces in pediatric endocrinology;Molecular and Cellular Endocrinology;2021-09

4. Aldosterone Receptors;Encyclopedia of Endocrine Diseases;2018

5. MicroRNA-31 promotes adverse cardiac remodeling and dysfunction in ischemic heart disease;Journal of Molecular and Cellular Cardiology;2017-11

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