Abrogation of FGFR signaling blocks β-catenin–induced adrenocortical hyperplasia and aldosterone production
Vasileios Chortis, Dulanjalee Kariyawasam, Mesut Berber, Nick A. Guagliardo, Sining Leng, Betul Haykir, Claudio Ribeiro, Manasvi S. Shah, Emanuele Pignatti, Brenna Jorgensen, Lindsey Gaston, Paula Q. Barrett, Diana L. Carlone, Kleiton Silva Borges, David T. Breault
Vasileios Chortis, Dulanjalee Kariyawasam, Mesut Berber, Nick A. Guagliardo, Sining Leng, Betul Haykir, Claudio Ribeiro, Manasvi S. Shah, Emanuele Pignatti, Brenna Jorgensen, Lindsey Gaston, Paula Q. Barrett, Diana L. Carlone, Kleiton Silva Borges, David T. Breault
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Research Article Cardiology Endocrinology

Abrogation of FGFR signaling blocks β-catenin–induced adrenocortical hyperplasia and aldosterone production

Abstract

Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors critical for organogenesis and tissue maintenance, including in the adrenal gland. Here we delineate the role of FGFR2 in the morphogenesis, maintenance, and function of the adrenal cortex with a focus on the zona glomerulosa (zG). zG-specific Fgfr2 deletion (Fgfr2-cKO) resulted in impaired zG cell identity, proliferation, and transdifferentiation into zona fasciculata (zF) cells during postnatal development. In adult mice, induced deletion of Fgfr2 led to loss of mature zG cell identity, highlighting the importance of FGFR2 for the maintenance of a differentiated zG state. Strikingly, Fgfr2-cKO was sufficient to fully abrogate β-catenin–induced zG hyperplasia and to reduce aldosterone levels. Finally, short-term treatment with pan-FGFR small molecule inhibitors suppressed aldosterone production in both WT and β-catenin gain-of-function mice. These results demonstrate a critical role for FGFR signaling in adrenal morphogenesis, maintenance, and function and suggest that targeting FGFR signaling may benefit patients with aldosterone excess and/or adrenal hyperplasia.

Authors

Vasileios Chortis, Dulanjalee Kariyawasam, Mesut Berber, Nick A. Guagliardo, Sining Leng, Betul Haykir, Claudio Ribeiro, Manasvi S. Shah, Emanuele Pignatti, Brenna Jorgensen, Lindsey Gaston, Paula Q. Barrett, Diana L. Carlone, Kleiton Silva Borges, David T. Breault

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Figure 3

Fgfr2 deletion abrogates β-catenin–induced zG hyperplasia.

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Fgfr2 deletion abrogates β-catenin–induced zG hyperplasia. (A) Represen...
(A) Representative images of GFP (green) and DAB2 (red) immunostaining of Ctrl (ASCre/+ R26RmTmG/+), βCat-GOF, and βCat-GOF Fgfr2-cKO adrenal glands from adult mice (6–10 weeks). (B) Quantification of GFP+ cells as a proportion of total cells in the zG (left) and the zF (right) in adult male and female mice (6–10 weeks). One-way ANOVA, ***P < 0.001, ****P < 0.0001, n = 5–7 per group. (C) Quantification of DAB2+ cells in the zG of adult male and female mice (6–10 weeks). One-way ANOVA with post hoc Tukey’s test, ****P < 0.0001, n = 5–7 per group. (D) Representative images of GFP (green) and AS (red) immunostaining of Ctrl, βCat-GOF, and βCat-GOF Fgfr2-cKO adrenal glands from adult mice (6–10 weeks). (E) Quantification of AS+ cells in the zG of adult male and female mice. One-way ANOVA with post hoc Tukey’s test, **P < 0.01, ****P < 0.0001, n = 5–7 per group. Adrenal glands from male mice are represented with black dots; adrenal glands from female mice are represented with magenta dots (B, C, and E). (F) Mean 24-hour urine aldosterone corrected for creatinine in male Ctrl, βCat-GOF, and βCat-GOF Fgfr2-cKO mice (6–20 weeks). Mice were fed with normal chow for 4 days, followed by low-sodium chow for 6 days. Urine was collected daily for days 1–4 (regular diet, normal sodium) and 8–11 (low sodium). One-way ANOVA with post hoc Tukey’s test, *P < 0.05, **P < 0.01, ****P < 0.0001, n = 5–7 per group. Scale bars: 50 μm. DAPI (blue), nuclei. Dashed white lines correspond to the zG-zF boundary.