Decreased sensitivity of distal nephron and collecting duct to parathyroidhormone in pseudohypoparathyroidism type I

Parathyroid hormone (PTH) transiently increases urinary excretion of the ly sosomal enzyme, N-acetyl-p-D-glucosaminidase, which is distributed mainly i n proximal tubules. The response is reduced in pseudohypoparathyroidism (PH P) type I, which is characterized by target-organ resistance to PTH. Eviden ced by normal calcium resorption, distal tubule sensitivity to PTH has been believed to be normal in this disorder. This hypothesis was tested through a search for another marker of distal nephron sensitivity to PTH. In the h uman kidney, cathepsin D was expressed predominantly in distal segments of the nephron, cortical and medullary thick ascending limbs of Henle's loop, distal convoluted tubules, and connecting tubules and in cortical collectin g ducts and medullary collecting ducts. PTH infusion transiently increased cathepsin D excretion in normal subjects. The cathepsin D response to PTH w as reduced in the patients with PHP type I. The decrease in cathepsin D res ponse in PHP type I indicates a resistance to PTH in the distal nephron (co rtical thick ascending limbs of Henle's loop, distal convoluted tubules, an d connecting tubules) and cortical collecting ducts. These observations sug gest that the preservation of renal tubular sensitivity to PTH in this diso rder may be confined to PTH-dependent calcium resorption in distal tubules.