Journal of Human Hypertension | 2021
Renal tubular transport protein regulation in primary aldosteronism: can large-scale proteomic analysis offer a new insight?
Abstract
Primary aldosteronism was firstly described by the American physician Jerome W. Conn in 1955 [1]. He reported a case of a young woman with severe hypertension, hypokalemia, and an aldosterone-producing adrenal adenoma. Conn ascribed this clinical entity to the aldosterone excess from the adrenal adenoma that in turn activated mineralocorticoid receptors in the aldosterone-sensitive parts of distal nephron, resulting in Na reabsorption, and K and H + excretion, that is a major alteration in renal electrolyte handling. Since then, primary aldosteronism has seen intensive research efforts into several aspects, such as the epidemiology, genetic background, clinical features, diagnostic work-up, subtype classification, target-organ damage, and treatment [2]. Currently, primary aldosteronism is documented as one of the most common, treatable form of secondary hypertension that becomes more prevalent in the setting of resistant hypertension; it is also well established that patients with primary aldosteronism have more pronounced cardiovascular and renal injury compared with patients with primary hypertension [3–6]. A recently published meta-analysis of more than 15,000 hypertensive individuals (including 6056 patients with primary aldosteronism), showed that patients with primary aldosteronism had a higher estimated glomerular filtration rate, and more severe albuminuria compared with non-aldosteronic hypertensive participants, a finding indicative of more pronounced damage associated with glomerular hypertension and hyperfiltration in the former [6]. Despite of many advances in the field of primary aldosteronism, the molecular basis of the altered renal electrolyte handling remains not fully determined; furthermore, relevant data mainly derive from in vitro and animal studies, with human studies being relatively scarce. In humans, the aldosterone-sensitive nephron includes the final parts of the distal convoluted tubule, the connecting tubule, and the cortical collecting duct. A wide cluster of transporters and channels participate in ion exchange, including the epithelial sodium channel (EnaC), sodium chloride cotransporter (NCC), the renal outer medullary K+ channel (ROMK), pendrin, Na/K-ATPase, potassium chloride channel 4, big potassium channel, inward rectifying potassium channels 4.1 and 5.1, H+-ATPase, and others [7]. In primary aldosteronism, aldosterone excess stimulates ENaC and ROMK activity, and enhances NCC and pendrin apical abundance [7–9]. From a clinical perspective, the abovementioned alterations of tubular ion exchange result in hypertension with increased total body Na, hypokalemia, and metabolic alkalosis. Pendrin is a Na-independent Cl/HCO3 − exchanger located in the apical membrane of type B, non-A, and nonB intercalated cells in the aldosterone-sensitive distal nephron. Pendrin helps control urinary acidification and thereby helps prevent metabolic alkalosis by facilitating HCO3 − secretion and Cl absorption. Furthermore, pendrin expression is necessary for normal ENaC expression and activity in type B intercalated cells. Over the last years, pendrin has emerged as a potential drug target for volume overload. Early studies in mice showed that knock-out of pendrin leads to greater losses of Na and Cl and reduction in blood pressure levels [10, 11], while mice overexpressing pendrin have Cl-sensitive hypertension, with blood pressure very sensitive to Cl intake [12]. However, the use of a pendrin inhibitor in animals failed to provide higher sodium urinary excretion and blood pressure decrease [13]. In addition, pendrin inhibition was associated with decreased sensitivity to the actions of thiazides, while in contrast, it enhanced both the natriuretic and kaliuretic effects of furosemide without any sign of acid-base perturbation [13]. Furthermore, the impact of pendrin * Konstantinos Stavropoulos [email protected]