Feline hyperaldosteronism: immunohistochemical, genetic and functional characterisation of the adrenal gland in hypertensive cats
Professor Harriet Syme, Clinical Science and Services, Royal Veterinary College
Professor Morris Brown, The William Harvey Research Institute - Barts and The London, Queen Mary, University of London
Dr Philip Watson, Boehringer Ingelheim
Hypertension is a common problem in geriatric cats, particularly those with renal disease and often results in blindness. Improved understanding of the pathogenesis of feline hypertension could result in earlier identification of those cats that are most at risk, or lead to novel targets for treatment. Hyperaldosteronism is the most common, curable cause of hypertension in humans and recently, state-of-the-art molecular analyses (sequencing, gene-expression, immunocytochemistry, and imaging) have transformed understanding of this disease.
Geriatric cats commonly have micronodular hyperplasia of their adrenal glands. We postulate that hyper-functional, aldosterone-producing, adrenal nodules play a major role in the pathogenesis of feline hypertension. This is supported by the observation that cats with hypertension have lower plasma potassium, and higher aldosterone concentrations, than age-matched normotensive cats with comparable severity of azotaemia. As such, there are clear parallels between cats and humans. Classically most humans with primary hyperaldosteronism have been considered to have either aldosterone-producing adenomas (APA) or bilateral adrenal hyperplasia. Recent improvements in phenotypic and genotypic characterisation have shown that this classification is an over-simplification. Even in adrenal glands containing APAs the surrounding tissue may not be atrophied, but contain multiple smaller nodules. In addition, the zonation of the APAs may be unexpected with some of the larger APAs residing in the zona fasiculata, rather in the zona glomerulosa. Classification of APAs in humans has now advanced to the molecular level with the recognition of somatic mutations in inward rectifier potassium channel 4 (KCNJ5), the voltage-gated calcium channel (CACNA1D), Na+/K+-ATPase (ATP1A1), Ca2+-ATPase (ATP2B3) and β-catenin (CTNNB1). Receptors for luteinizing hormone (LH) have been demonstrated in human adrenal glands and their expression may be increased in APAs. This is of interest because most cats are neutered and this results in increased LH concentrations and it is postulated that activation of these receptors could result in adrenal hyperplasia.
A small number of hypertensive cats present with overt signs of ‘Conn’s syndrome’ with severe hypokalaemic myopathy resulting in cervical ventroflexion and with an identifiable, surgically-resectable, adrenal mass. Other types of functional adrenal tumour including those resulting in hypercortisolism and excessive production of sex-steroids are less common. Interestingly, it seems likely that cats (like dogs) have only one CYP11B gene, resulting in the production of a single dual-function enzyme rather than separate aldosterone synthase and 11-beta hydroxylase (cortisol synthase) as occurs in humans. This leads to the question of how (or indeed if) functional zonation, and independently regulated synthesis of cortisol and aldosterone, occurs in the cat in health and how this might be altered when hyperplasia or adenoma develop.
We hypothesise that:
- 1. Functional zonation of the feline adrenal gland is dependent on CYP17A1 expression
- 2. Adrenal hyperplasia is common in all geriatric cats, but cats with hypertension will be more likely to have APAs
- 3. These APAs will be heterogeneous containing different somatic mutations
To test these hypotheses this project will involve the following:
- Clinical enrolment of normotensive and hypertensive cats through the geriatric cat clinic (although there is also an established resource of stored blood samples and histopatholgical specimens from cats seen previously).
- Recruitment of histological sections from cats with well-characterised adrenal tumours treated in referral hospitals
- Measurement of aldosterone in stored
Large adrenal tumour causing hyperaldosteronism at post-mortem examination
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- Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C, Garg S, Bochukova EG, Zhao W, Shaikh LH, Brighton CA, Teo AE, Davenport AP, Dekkers T, Tops B, Kusters B, Ceral J, Yeo GS, Neogi SG, McFarlane I, Rosenfeld N, Marass F, Hadfield J, Margas W, Chaggar K, Solar M, Deinum J, Dolphin AC, Farooqi IS, Striessnig J, Nissen P and Brown MJ. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet. 2013; 45(9): 1055-60.
- Teo AED, Garg S, Haris Shaikh L, Zhou J, Karet Frankl FE, Gurnell M, Happerfield L, Marker A, Bienz M, Azizan EAB, Brown MJ. Pregnancy, Primary Aldosteronism, and Adrenal CTNNB1 Mutations. New England Journal of Medicine. 2015; 373:1429-1436.
eligibility and application
Applicants must hold, or be expected to achieve, a first or high upper second-class undergraduate honours degree or equivalent (for example BA, BSc, MSci) or a Masters degree in a relevant subject. This project is funded by a 4-year BBSRC studentship, applicants should ensure they have understood the funding eligibility criteria for these studentships. Unfortunately international students are not eligible for programme funding on this project.
Veterinary-qualified applicants receive an enhanced stipend of £23,164
For more information regarding the project, please contact Professor Harriet Syme
Download the APPLICATION GUIDELINES here.