An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D-3

Steroid hormones may enter cells by diffusion through the plasma membrane. However, we demonstrate here that some steroid hormones are taken up by rec eptor-mediated endocytosis of steroid-carrier complexes. We show that 25-(O H) vitamin D-3 in complex with its plasma carrier, the vitamin D-binding pr otein, is filtered through the glomerulus and reabsorbed in the proximal tu bules by the endocytic receptor megalin. Endocytosis is required to preserv e 25-(OH) vitamin D-3 and to deliver to the cells the precursor for generat ion of 1,25-(OH)(2) Vitamin D-3, a regulator of the calcium metabolism. Meg alin(-/-) mice are unable to retrieve the steroid from the glomerular filtr ate and develop vitamin D deficiency and bone disease.