Abstract | KEY POINTS: The reabsorptive activity of renal proximal tubule cells is mediated by receptor-mediated endocytosis and polarized transport systems that reflect final cell differentiation. Loss-of-function mutations of the endosomal chloride- proton exchanger ClC-5 ( Dent's disease) cause a major trafficking defect in proximal tubule cells, associated with lysosomal dysfunction, oxidative stress and dedifferentiation/proliferation. A similar but milder defect is associated with mutations in CFTR ( cystic fibrosis transmembrane conductance regulator). Vesicular chloride transport appears to be important for the integrity of the endolysosomal pathway in epithelial cells. ABSTRACT: The epithelial cells lining the proximal tubules of the kidney reabsorb a large amount of filtered ions and solutes owing to receptor-mediated endocytosis and polarized transport systems that reflect final cell differentiation. Dedifferentiation of proximal tubule cells and dysfunction of receptor-mediated endocytosis characterize Dent's disease, a rare disorder caused by inactivating mutations in the CLCN5 gene that encodes the endosomal chloride- proton exchanger, ClC-5. The disease is characterized by a massive urinary loss of solutes ( renal Fanconi syndrome), with severe metabolic complications and progressive renal failure. Investigations of mutations affecting the gating of ClC-5 revealed that the proximal tubule dysfunction may occur despite normal endosomal acidification. In addition to defective endocytosis, proximal tubule cells lacking ClC-5 show a trafficking defect in apical receptors and transporters, as well as lysosomal dysfunction and typical features of dedifferentiation, proliferation and oxidative stress. A similar but milder defect is observed in mouse models with defective CFTR, a chloride channel that is also expressed in the endosomes of proximal tubule cells. These data suggest a major role for endosomal chloride transport in the maintenance of epithelial differentiation and reabsorption capacity of the renal proximal tubule.
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Authors | Olivier Devuyst, Alessandro Luciani |
Journal | The Journal of physiology
(J Physiol)
Vol. 593
Issue 18
Pg. 4151-64
(Sep 15 2015)
ISSN: 1469-7793 [Electronic] England |
PMID | 25820368
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
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Copyright | © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society. |
Chemical References |
- Chloride Channels
- Chlorides
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Topics |
- Animals
- Chloride Channels
(metabolism)
- Chlorides
(metabolism)
- Endocytosis
(physiology)
- Endosomes
(metabolism)
- Epithelial Cells
(metabolism)
- Humans
- Ion Transport
(physiology)
- Kidney Tubules, Proximal
(metabolism, physiology)
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