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

高血压是老年猫的常见问题，特别是那些有肾脏疾病的猫。直到猫出现不可逆的失明，才会被发现。患有高血压的猫的血浆钾较低，醛固酮浓度较高，与患有严重氮血症的同龄正常猫相比。老年猫（血压正常和高血压）通常有肾上腺小结节增生。我们假设功能亢进的醛固酮分泌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。传统上，大多数原发性醛固酮增多症患者被认为患有醛固酮生成腺瘤（APA）或双侧肾上腺增生。最近在表型和基因型特征的改进表明，这种分类是一种过度简化。即使在含有APAs的肾上腺，其周围组织也可能不萎缩，但含有多个较小的结节。此外，APAs的分带性可能出乎意料，一些较大的APAs位于束状带，而不是肾小球带。人类APAs的分类现已发展到分子水平，识别出了向内整流钾通道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）的体细胞突变。促黄体生成素受体（LH）已在人肾上腺中被证实，其表达可能在APAs中增加。这是很有趣的，因为大多数猫都是绝育的，这导致黄体生成素浓度增加，并且假设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“康氏综合征”症状，伴有严重的低钾血症性肌病，导致颈椎腹曲，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，包括那些导致高皮质醇血症和性类固醇过度产生的肿瘤，不太常见。一些猫科动物的肾上腺肿瘤具有复杂的功能。有趣的是，猫（像狗一样）似乎只有一个CYP11B基因，导致产生单一的双重功能酶，而不是像人类那样产生单独的醛固酮合成酶和11- β羟化酶（皮质醇合成酶）。这就引出了一个问题，即功能分区和独立调节的皮质醇和醛固酮的合成是如何（或者是否）在健康的猫身上发生的，以及当增生或腺瘤发生时，这可能会如何改变。

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.