ADAM17, a New Player in the Pathogenesis of Chronic Kidney Disease-Mineral and Bone Disorder

The triad composed by α-Klotho, fibroblast growth factor-23, and its receptor are involved in the pathogenesis of chronic kidney disease-mineral and bone disorder. A disintegrin and metalloproteinase 17 (ADAM17) is a metalloproteinase causing the proteolytic shedding of α-Klotho from the cell membrane, and its role in chronic kidney disease-mineral and bone disorder is not yet known. We studied the circulating levels of the above-mentioned mediators in patients with secondary hyperparathyroidism due to uremia, compared to control subjects, as well as in patients with primary hyperparathyroidism. We also measured the immunofluorescence pattern of the relevant tissue proteins in specimens obtained from patients undergoing parathyroid surgery for secondary compared to primary hyperparathyroidism. Results showed that α-Klotho tissue levels are reduced, in the presence of increased ADAM17 tissue levels. In addition, we showed increased serum levels of the main product of ADAM17 proteolytic activity, tumor necrosis factor-α. Thus, we found a paradoxical situation, in secondary compared to primary hyperparathyroidism, that is, that in the face of increased tumor necrosis factor-α in circulation, both soluble and tissue α-Klotho are reduced significantly, despite increased tissue ADAM17. In conclusion, tissue and serum levels of α-Klotho seem to have become independent from the regulation induced by ADAM17, which constitutes therefore another tassel in the impaired α-Klotho-FGF23 receptor axis present in uremia.