Claudin Function in the Thick Ascending Limb of Henle's Loop

During the past decade, claudins have been established as major determinants of paracellular permeablilty in epithelia. In the kidney, each nephron segment expresses a distinct pattern of claudins. Cells of the thick ascending limb of Henle's loop (TAL), which is characterized by high paracellular cation permeability, co-express an unusually large number of different claudins: claudin-10, -16, and -19 and, depending on the species, also claudin-3, -4, -8, and/or -11. The function of most of these claudins has been investigated in vitro. We present a summary of their function with special emphasis on claudin-16 and -19. Mutations in the corresponding human genes lead to severely impaired renal Ca2+ and Mg2+ handling. To date, 42 different claudin-16 mutations and three claudin-19 mutations have been reported. These mutations prevent the claudins from reaching the surface membrane, decrease membrane residence time, or render them functionless. In spite of the clear clinical symptoms such as hypomagnesemia, hypercalciuria, nephrocalcinosis, and renal insufficiency, mechanisms that link claudin-16 and -19 to these symptoms are still unknown. Depending on the cell type used in overexpression studies, claudin-16 appears to cause a mild increase in paracellular Mg2+-permeability or a pronounced increase in Na+ permeability. Claudin-19 selectively decreases Cl- permeability, thus synergistically increasing relative cation permeability, or indiscriminately decreases paracellular permeability. In the light of these results it is hypothesized that the renal Mg2+/Ca2+ waste may not be solely due to reduced resorption in the TAL but at least in part to paracellular back-leak of Mg2+/Ca2+ into the tubular lumen of the distal convoluted tubule.