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 Ca(2+) and Mg(2+) 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 Mg(2+)-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 Mg(2+)/Ca(2+) waste may not be solely due to reduced resorption in the TAL but at least in part to paracellular back-leak of Mg(2+)/Ca(2+) into the tubular lumen of the distal convoluted tubule.
Günzel
Dorothee
D
Institute of Clinical Physiology, Charité, Berlin, Germany. dorothee.guenzel@charite.de
Haisch
Lea
L
Pfaffenbach
Sandra
S
Krug
Susanne M
SM
Milatz
Susanne
S
Amasheh
Salah
S
Hunziker
Walter
W
Müller
Dominik
D
D000818:Animals; D002463:Cell Membrane Permeability; D006801:Humans; D053565:Hypercalciuria / Q000378:metabolism; D008138:Loop of Henle / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009397:Nephrocalcinosis / Q000378:metabolism
D008565:Membrane Proteins