2024
Endocrinology. 2024 Mar 29;165(5):bqae040. doi: 10.1210/endocr/bqae040.
Zona Glomerulosa-Derived Klotho Modulates Aldosterone Synthase Expression in Young Female Mice
Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital of Zürich (USZ) and University of Zürich (UZH), 8091 Zurich, Switzerland. Institute of Clinical Chemistry and Laboratory Medicine, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany. Institute of Anatomy, University of Zürich, 8057 Zurich, Switzerland. Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electrophysiology Facility, University of Zurich, 8057 Zürich, Switzerland. Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität, 81377 Munich, Germany. The LOOP Zurich Medical Research Center, 8044 Zurich, Switzerland.
Service type: Knockout mice
Abstract
Klotho plays a critical role in the regulation of ion and fluid homeostasis. A previous study reported that haplo-insufficiency of Klotho in mice results in increased aldosterone synthase (CYP11B2) expression, elevated plasma aldosterone, and high blood pressure. This phenotype was presumed to be the result of diminished Klotho expression in zona glomerulosa (zG) cells of the adrenal cortex; however, systemic effects on adrenal aldosterone production could not be ruled out. To examine whether Klotho expressed in the zG is indeed a critical regulator of aldosterone synthesis, we generated a tamoxifen-inducible, zG-specific mouse model of Klotho deficiency by crossing Klotho-flox mice with Cyp11b2-CreERT mice (zG-Kl-KO). Tamoxifen-treated Cyp11b2-CreERT animals (zG-Cre) served as controls. Rosa26-mTmG reporter mice were used for Cre-dependent lineage-marking. Two weeks after tamoxifen induction, the specificity of the zG-Cre line was verified using immunofluorescence analysis to show that GFP expression was restricted to the zG. RNA in situ hybridization revealed a 65% downregulation of Klotho messenger RNA expression in the zG of zG-Kl-KO female mice at age 12 weeks compared to control mice. Despite this significant decrease, zG-Kl-KO mice exhibited no difference in plasma aldosterone levels. However, adrenal CYP11B2 expression and the CYP11B2 promotor regulatory transcription factors, NGFIB and Nurr1, were enhanced. Together with in vitro experiments, these results suggest that zG-derived Klotho modulates Cyp11b2 but does not evoke a systemic phenotype in young adult mice on a normal diet. Further studies are required to investigate the role of adrenal Klotho on aldosterone synthesis in aged animals.
Keywords: CYP11B2; Cre-lox system; Klotho; aldosterone; zona glomerulosa.
