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

猫醛固酮增多症：高血压猫肾上腺的免疫组织化学、遗传和功能特征

• 批准号: 2401643
• 金额: --
• 依托单位: Royal Veterinary College
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2401643
• 关键词: Feline; hyperaldosteronism; immunohistochemical; genetic; functional

Hypertension is a common problem in geriatric cats, particularly those with renal disease. It is often not recognised until the cat is presented with irreversible blindness. Cats with hypertension have lower plasma potassium, and higher aldosterone concentrations, than age-matched normotensive cats with comparable severity of azotaemia.Geriatric cats (both normotensive and hypertensive) 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. 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), Sodium/Potassium-ATPase (ATP1A1), Ca2+-ATPase (ATP2B3) and Beta-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. Some feline adrenal tumours have mixed functionality. 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.

高血压是老年猫的常见问题，尤其是患有肾脏疾病的猫。直到猫出现不可逆转的失明时，通常才会被识别出来。与年龄匹配、血压正常、氮血症严重程度相当的猫相比，患有高血压的猫的血浆钾较低，醛固酮浓度较高。老年猫（血压正常和高血压）的肾上腺通常有微结节性增生。我们假设功能亢进、产生醛固酮的肾上腺结节在猫高血压的发病机制中起主要作用。因此，猫和人类之间有明显的相似之处。通常，大多数患有原发性醛固酮增多症的人被认为患有产生醛固酮的腺瘤（APA）或双侧肾上腺增生。最近表型和基因型表征的改进表明这种分类过于简单化。即使在含有 APA 的肾上腺中，周围组织也可能不会萎缩，而是含有多个较小的结节。此外，APA 的分区可能是出乎意料的，一些较大的 APA 位于束状带，而不是肾小球带。随着内向整流钾通道 4 (KCNJ5)、电压门控钙通道 (CACNA1D)、钠/钾-ATP 酶 (ATP1A1)、Ca2+-ATP 酶 (ATP2B3) 和 β-连环蛋白 (CTNNB1) 体细胞突变的识别，人类 APA 的分类现已发展到分子水平。黄体生成素 (LH) 受体已在人类肾上腺中得到证实，并且它们的表达在 APA 中可能会增加。这很有趣，因为大多数猫都被绝育，这会导致 LH 浓度增加，并且推测这些受体的激活可能导致肾上腺增生。少数高血压猫表现出明显的“康恩综合征”症状，伴有严重的低钾血症性肌病，导致颈椎腹屈，并伴有可识别的、可手术切除的肾上腺肿块。其他类型的功能性肾上腺肿瘤，包括导致皮质醇增多症和性类固醇过度产生的肿瘤，则不太常见。一些猫科动物肾上腺肿瘤具有混合功能。有趣的是，猫（如狗）似乎只有一个 CYP11B 基因，从而产生一种双功能酶，而不是像人类那样产生单独的醛固酮合酶和 11-β 羟化酶（皮质醇合酶）。这就引出了一个问题：功能分区以及皮质醇和醛固酮的独立调节合成如何（或者是否）在健康的猫中发生，以及当增生或腺瘤发生时，这可能如何改变。