Abstract: SA-PO321
Adrenal Hyperplasia, Hormonal Disturbance, and Salt-Sensitive Hypertension in a Novel Rat Model with Glucocorticoid Resistance Syndrome
Session Information
- Hypertension and CVD: Mechanisms
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- Vanderriele, Paul emmanuel, University of Lausanne, Lausanne, Switzerland
- Wang, Qing, CHUV, Lausanne, Switzerland
- Ancin, David, UNIL, Lausanne, Switzerland
- Ino, Frederique, University of Lausanne, Lausanne, Switzerland
- Kratschmar, Denise V., University of Basel, Basel, Switzerland
- Odermatt, Alex, University of Basel, Basel, Switzerland
- Kellenberger, Stephan, University of Lausanne, Lausanne, Switzerland
- Hummler, Edith, University of Lausanne, Lausanne, Switzerland
- Verouti, Sofia N., University of Lausanne, Lausanne, Switzerland
Group or Team Name
- Professor Edith Hummler
Background
Glucocorticoid resistance is often due to glucocorticoid receptor (GR) haploinsufficiency, and is characterized by partial target tissue resistance to glucocorticoids. In human, an elevation in circulating glucocorticoids may cause the development of hypertension and, in some cases, obesity and sterility.
Methods
So far, no animal model mimics all features observed in human generalized glucocorticoid resistance. To address the impact of GR haploinsufficiency on adrenal gland function, steroid expression and development of hypertension, we generated rats carrying a deletion within the second zinc finger of the GR, named GR+/em2 (Ponce de León. V et al; Plos One, 2014).
Results
Heterozygous mutant GR+/em2 rats showed a monolateral adrenal hyperplasia with hyperkalemia, an increase of plasmatic aldosterone (0,47 ± 0,018 nM vs 0,39 ± 0,019nM pm, p<0,01), plasmatic corticosterone (576 ± 88,96 nM vs 332 ± 75,45 nM am, p<0,05; 1000 ± 61,41 nM vs 615 ± 99,11 nM pm, p<0,05), plasmatic 11-deoxycorticosterone (76,6 ± 5,24 nM vs 50,3 ± 5,97 nM am, p<0,001; 101,8 ± 4,02 nM vs 74,6 ± 5,63 nM pm, p<0,01) despite a normal activity of the 11-β-hydroxysteroid-dehydrogenase II (GR+/+= 15, GR+/em2= 8). Furthermore, GR+/em2 mutant rats develop salt-sensitive hypertension followed by an increase of adrenal and kidney weight. In addition, RNA-seq analysis reveals disturbances in 41 genes (21 up, 20 down regulated) implicated in e.g, adrenal gland architecture and steroid biosynthesis. We currently focus on these identified candidate genes implicated in adrenal gland function and we perform electrophysiological measurements on primary adrenal cells upon stimulation with angiotensin II and potassium chloride to determine the cell depolarization capacity in these cells.
Conclusion
In summary, we demonstrated that GR+/em2 mutant rats are useful to study GR haploinsufficiency and the underlying mechanism leading to adrenal gland hyperplasia. We confirm the role of the GR in the development of salt-sensitive hypertension. We are currently studying identified new candidate genes leading to salt-sensitive hypertension in this rat model.
Funding
- Government Support - Non-U.S.