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，尤其是患有肾病的猫。它往往是不承认，直到猫是不可逆转的失明。与年龄匹配的血压正常的猫相比，患有高血压的猫具有较低的血浆钾和较高的醛固酮浓度，而血压正常的猫具有相似的氮质血症严重程度。老年猫（血压正常和高血压）通常具有肾上腺的小结节增生。我们推测，功能亢进，醛固酮生成，肾上腺结节在猫高血压的发病机制中发挥了重要作用。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腺瘤（阿帕）或双侧肾上腺增生。最近在表型和基因型表征方面的改进表明，这种分类过于简单化。即使在含有APA的肾上腺中，周围组织可能不会萎缩，但含有多个较小的结节。此外，APA的分区可能是意想不到的，一些较大的APA居住在扁囊藻中，而不是在小球藻中。随着对内向整流钾通道4（KCNJ 5）、电压门控钙通道（CACNA 1D）、钠/钾-ATP酶（ATP 1A 1）、Ca 2 +-ATP酶（ATP 2B 3）和β-连环蛋白（CTNNB 1）的体细胞突变的识别，人类APA的分类现已发展到分子水平。已证明人类肾上腺中存在促黄体生成素（LH）受体，并且它们在APA中的表达可能会增加。这一点很有意义，因为大多数猫都是绝育的，这会导致LH浓度升高，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”体征，伴有严重的低钾血症性肌病，导致颈部腹屈，并伴有可识别的、可切除的肾上腺肿块。其他类型的功能性肾上腺肿瘤，包括那些导致皮质醇增多症和性类固醇过度生产是不常见的。一些猫肾上腺肿瘤具有混合功能。有趣的是，猫（像狗一样）似乎只有一个CYP 11B基因，导致产生一个单一的双功能酶，而不是像人类那样单独的醛固酮合成酶和11-β羟化酶（皮质醇合成酶）。这就引出了这样一个问题：在健康的猫中，皮质醇和醛固酮的功能分区以及独立调节的合成是如何发生的，以及当增生或腺瘤发生时，这种情况可能会如何改变。

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.