# Mechanisms Leading to Adrenal Zonation

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $431,567

## Abstract

Project Summary/Abstract
Background. The current proposal is a competitive renewal application that focuses on defining the
mechanisms causing zonation of the adrenal cortex. In the mammalian adrenal cortex, mineralocorticoids are
produced in the zona glomerulosa (ZG) and glucocorticoids in the zona fasciculata (ZF). Production of aldosterone
results from ZG-specific expression of the enzyme aldosterone synthase (Cyp11b2), while production of
glucocorticoids relies on ZF-specific expression of the closely related 11β-hydroxylase (Cyp11b1). In normal
physiology, the aldosterone production in the ZG is tightly regulated by the renin-angiotensin II system. However,
dysregulation of zonation with renin-independent aldosterone production and Cyp11b2 expression occurs in primary
aldosteronism (PA), a condition that affects 8% of hypertensive patients. The current proposal takes advantage of
our past molecular research on Cyp11b2 and moves our findings into in vivo models of mammalian zonation and
adrenal disease. Research goals. Specific Aim 1 will define the contribution of Dax1 (Nr0b1) in normal
adrenocortical zonation. Hypothesis for Aim 1: Dax1 expression is required for adrenal zone-specific Cyp11b2
and Cyp11b1 expression. Approach for Aim 1: Cell and mouse based approaches will be used to define the
interplay between Sf1 and Dax1 in the regulation of adrenal cell production of aldosterone (ZG phenotype) vs.
corticosterone (ZF phenotype). Primary cultures of mouse adrenal cells and the H295R human adrenocortical cell
line will be used to define the molecular mechanisms by which Sf1 and Dax1 cooperatively regulate gene expression
that defines ZG versus ZF steroid production. Mouse genetic models will be used to interrogate the sexual dimorphic
roles of Dax1 in adrenal zonation and corresponding ZG Cyp11b2 versus ZF Cyp11b1 expression. Specific Aim 2
will define mechanisms responsible for sex differences in adrenal aldosterone production and susceptibility to
PA. Hypothesis for Aim 2: The differential expression of the nuclear receptor Dax1 in female vs male adrenals
directly impacts Cyp11b2 expression, aldosterone production, and susceptibility to PA. Rationale for Aim 2:
Four mouse models of PA have shown greater disease susceptibility in females compared to males. In addition,
women have a higher prevalence of low renin hypertension and a higher aldosterone/renin ratio compared to
men. The molecular mechanisms controlling these differences are not known. Physiological manipulations and
transgenic mouse experiments are proposed to test hypotheses associated with both project aims.
Innovations. There are at least three key innovative components to the proposed research: 1) This will
represent the first development of an inducible mouse model of PA; 2) First research designed to define the role
for sexual dimorphism in adrenal zonation and PA; 3) First to apply broad based LC-MS/MS determination of
steroids (30 steroids) to define the steroid metabo...

## Key facts

- **NIH application ID:** 9959394
- **Project number:** 5R01DK043140-24
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** William E Rainey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $431,567
- **Award type:** 5
- **Project period:** 1994-08-01 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959394

## Citation

> US National Institutes of Health, RePORTER application 9959394, Mechanisms Leading to Adrenal Zonation (5R01DK043140-24). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9959394. Licensed CC0.

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