ClC-5: a chloride channel with multiple roles in renal tubular albumin uptake.
ClC-5 is a chloride (Cl(-)) channel expressed in renal tubules and is critical for normal tubular function. Loss of function nonsense or missense mutations in ClC-5 are associated with Dent's disease, a condition in which patients present with low molecular weight (LMW) proteinuria (including albuminuria), hypercalciuria and nephrolithiasis. Several key studies in ClC-5 knockout mice have shown that the proteinuria results from defective tubular reabsorption of proteins. ClC-5 is typically regarded as an intracellular Cl(-) channel and thus the defect in this receptor-mediated uptake pathway was initially attributed to the failure of the early endosomes to acidify correctly. ClC-5 was postulated to play a key role in transporting the Cl(-) ions required to compensate for the movement of H(+) during endosomal acidification. However, more recent studies suggest additional roles for ClC-5 in the endocytosis of albumin. ClC-5 is now known to be expressed at low levels at the cell surface and appears to be a key component in the assembly of the macromolecular complex involved in protein endocytosis. Furthermore, mutations in ClC-5 affect the trafficking of v-H(+)-ATPase and result in decreased expression of the albumin receptor megalin/cubulin. Thus, the expression of ClC-5 at the cell surface as well as its presence in endosomes appears to be essential for normal protein uptake by the renal proximal tubule.
Hryciw
Deanne H
DH
School of Biomedical Sciences, The University of Queensland, Brisbane, Qld 4072, Australia.
Ekberg
Jenny
J
Pollock
Carol A
CA
Poronnik
Philip
P
D000418:Albumins / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D018118:Chloride Channels / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D004705:Endocytosis; D006801:Humans; D015640:Ion Channel Gating; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D051379:Mice; D011507:Proteinuria / Q000209:etiology; D017457:Receptors, Albumin / Q000378:metabolism; D051437:Renal Insufficiency / Q000378:metabolism / Q000503:physiopathology
D000418:Albumins; C097503:CLC-5 chloride channel; D018118:Chloride Channels; D017457:Receptors, Albumin