Physiological roles of CLC Cl(-)/H (+) exchangers in renal proximal tubules

Pflugers Arch. 2009 May;458(1):23-37. doi: 10.1007/s00424-008-0597-z. Epub 2008 Oct 14.


The CLC gene family encodes Cl(-) channels or Cl(-)/H(+) exchangers. While our understanding of their structure-function relationship has greatly benefited from the crystal structure of bacterial homologues, human inherited diseases and knock-out mice were crucial in deciphering their physiological roles. Several vesicular CLC Cl(-)/H(+) exchangers are expressed in the proximal tubule (PT). ClC-5 mutations cause Dent's disease which is associated with low molecular weight proteinuria and kidney stones. ClC-5 knock-out mice revealed impaired endocytosis as the primary defect in Dent's disease. It extends to receptor-mediated and fluid-phase endocytosis and entails changes in calciotropic hormones that result in kidney stones. No renal functions could be assigned so far to ClC-3 and ClC-4, which are also expressed in PTs. Loss of ClC-7 or its beta-subunit Ostm1 entails lysosomal storage in the PT, in addition to the neuronal lysosomal storage and osteopetrosis that are the hallmarks of ClC-7/Ostm1 loss in mice and men.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Chloride Channels / genetics
  • Chloride Channels / physiology*
  • Endocytosis / physiology
  • Gene Expression
  • Humans
  • Hypercalciuria / etiology
  • Hypophosphatemia, Familial / etiology
  • Kidney Calculi / etiology
  • Kidney Tubules, Proximal / metabolism*
  • Kidney Tubules, Proximal / physiopathology
  • Membrane Proteins / physiology
  • Mice
  • Mice, Knockout


  • CLC-5 chloride channel
  • CLCN7 protein, human
  • Chloride Channels
  • Membrane Proteins
  • OSTM1 protein, mouse