Grant: CIHR Clinician Scientist - Phase 2

We aim to understand how the kidney prevents urinary calcium loss. A failure to do this can result in kidney stones and/or thin bones (osteoporosis) The inappropriate loss of calcium in the urine is called hypercalciuria. We seek to determine the mechanism by which hypercalciuria occurs, so as to be able to develop specific treatments for kidney stones and osteoporosis. Calcium in our blood is filtered by the glomerulus. In order for it not to be wasted in the urine it must be reabsorbed back into the blood by the renal tubule. The majority of this takes place in the first part of the renal tubule or proximal tubule. This is also the part of the tubule which fails to completely reabsorb calcium in people with hypercalciuria. We therefore seek to understand how calcium is reabsorbed from the proximal tubule. Calcium, in this part of the tubule, moves between the tubular cells. However, what allows calcium to move between these cells but prevents the movement of other molecules is not known. What has been recently appreciated is that a group of proteins form very specific pores between cells throughout tubular organs of the body. These proteins are called claudins. Specific pore forming claudins control the movement of molecules between cells. Unfortunately we do not know which claudins are in the proximal tubule. We will therefore first identify what claudins are in the proximal tubule. Next we will infer a role for these claudins in calcium homeostasis by feeding mice a low calcium diet and examining how much of these claudins are in the proximal tubule. We will also examine claudin expression after perturbing calcium homeostasis by administering hormones that alter tubular calcium handling. This will provide us with candidates whose calcium permeability will be tested in a cell culture model. These studies will provide insight into, and novel therapeutic targets for, the treatment of hypercalciuria, kidney stones and osteoporosis.