Increased parathyroid expression of klotho in uremic rats

Klotho is a protein of significant importance for mineral homeostasis. It helps to increase parathyroid hormone (PTH) secretion and in the trafficking of Na+/K+-ATPase to the cell membrane; however, it is also a cofactor for fibroblast growth factor (FGF)-23 to interact with its receptor, FGFR1 IIIC, resulting in decreased PTH secretion. Studies on the regulation of parathyroid klotho expression in uremia have provided varying results. To help resolve this, we measured klotho expression in the parathyroid and its response to severe uremia, hyperphosphatemia, and calcitriol treatment in the 5/6 nephrectomy rat model of secondary hyperparathyroidism. Parathyroid klotho gene expression and protein were significantly increased in severely uremic hyperphosphatemic rats, but not affected by moderate uremia and normal serum phosphorus. Calcitriol suppressed klotho gene and protein expression in severe secondary hyperparathyroidism, despite a further increase in plasma phosphate. Both FGFR1 IIIC and Na+/K+-ATPase gene expression were significantly elevated in severe secondary hyperparathyroidism. Parathyroid gland klotho expression and the plasma calcium ion concentration were inversely correlated. Thus, our study suggests that klotho may act as a positive regulator of PTH expression and secretion in secondary hyperparathyroidism.