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Feline hyperaldosteronism: immunohistochemical, genetic and functional characterisation of the adrenal gland in hypertensive cats


Project Description

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 blood and/or urine samples
• Characterisation of feline adrenal glands using light microscopy, immunohistochemistry and RT-PCR
• Laser capture microdissection of adrenal nodules
• Targeted sequencing of genes that have somatic mutations in human APAs

This project is a new collaboration between two established research groups with complementary expertise: the RVC - feline clinical research and QMUL – molecular characterisation of APAs in humans. As a result the successful candidate will be required to spend time working in both locations. In addition, the student will spend time on placement with the industrial sponsor Boehringer Ingelheim, both in Bracknell, Berkshire and at the company headquarters in Ingelheim am Rhein, in Germany. This pharmaceutical company is one of very few where human and animal health research and development occur in the same location. The student will use their time on placement to investigate the potential role, and barriers to, use of companion animals with spontaneous disease in translational research.
The clinical component of this project means that only applications from qualified veterinary surgeons will be accepted.

Applications

Applications must be complete, including both references, by 5pm, 24th January 2020

Funding Notes

Fully funded place including home (UK) tuition fees and a tax-free stipend of £23,164 for veterinary-qualified applicants. Students from the EU are welcome to submit an application for funding, any offers will be subject to BBSRC approval and criteria.

References

Syme HM, Barber PJ, Markwell PJ, Elliott J. Prevalence of systolic hypertension in cats with chronic renal failure at initial evaluation. J Am Vet Med Assoc. 2002; 220(12):1799-804.

Jepson RE, Syme HM, Elliott J. Plasma renin activity and aldosterone concentrations in hypertensive cats with and without azotemia and in response to treatment with amlodipine besylate. J Vet Intern Med. 2014; 28(1):144-53.

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.

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