Altered renal distal tubule structure and renal Na(+) and Ca(2+) handling in a mouse model for Gitelman's syndrome.

Détails

ID Serval
serval:BIB_7459AEFAA620
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Altered renal distal tubule structure and renal Na(+) and Ca(2+) handling in a mouse model for Gitelman's syndrome.
Périodique
Journal of the American Society of Nephrology
Auteur(s)
Loffing J., Vallon V., Loffing-Cueni D., Aregger F., Richter K., Pietri L., Bloch-Faure M., Hoenderop J.G., Shull G.E., Meneton P., Kaissling B.
ISSN
1046-6673 (Print)
ISSN-L
1046-6673
Statut éditorial
Publié
Date de publication
09/2004
Peer-reviewed
Oui
Volume
15
Numéro
9
Pages
2276-2288
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
Publication Status: ppublish
Résumé
Gitelman's syndrome, an autosomal recessive renal tubulopathy caused by loss-of-function mutations in the thiazide-sensitive NaCl co-transporter (NCC) of the distal convoluted tubule (DCT), is characterized by mild renal Na(+) wasting, hypocalciuria, hypomagnesemia, and hypokalemic alkalosis. For gaining further insights into the pathophysiology of Gitelman's syndrome, the impact of NCC ablation on the morphology of the distal tubule, on the distribution and abundance of ion transport proteins along its length, and on renal tubular Na(+) and Ca(2+) handling in a gene-targeted mouse model was studied. NCC-deficient mice had significantly elevated plasma aldosterone levels and exhibited hypocalciuria, hypomagnesemia, and compensated alkalosis. Immunofluorescent detection of distal tubule marker proteins and ultrastructural analysis revealed that the early DCT, which physiologically lacks epithelial Na(+) (ENaC) and Ca(2+) (TRPV5) channels, was virtually absent in NCC-deficient mice. In contrast, the late DCT seemed intact and retained expression of the apical ENaC and TRPV5 as well as basolateral Na(+)-Ca(2+) exchanger. The connecting tubule exhibited a marked epithelial hypertrophy accompanied by an increased apical abundance of ENaC. Ca(2+) reabsorption seemed unaltered in the distal convolution (i.e., the DCT and connecting tubule) as indicated by real-time reverse transcription-PCR, Western blotting, and immunohistochemistry for TRPV5 and Na(+)-Ca(2+) exchanger and micropuncture experiments. The last experiments further indicated that reduced glomerular filtration and enhanced fractional reabsorption of Na(+) and Ca(2+) upstream and of Na(+) downstream of the DCT provide some compensation for the Na(+) transport defect in the DCT and contribute to the hypocalciuria. Thus, loss of NCC leads to major structural remodeling of the renal distal tubule that goes along with marked changes in glomerular and tubular function, which may explain some of the clinical features of Gitelman's syndrome.

Mots-clé
Alkalosis/metabolism, Animals, Calcium/metabolism, Carrier Proteins/physiology, Disease Models, Animal, Kidney Diseases/genetics, Kidney Diseases/metabolism, Kidney Tubules, Distal/metabolism, Kidney Tubules, Distal/pathology, Magnesium/metabolism, Mice, Receptors, Drug/physiology, Sodium/metabolism, Sodium Chloride Symporters, Solute Carrier Family 12, Member 3, Symporters/physiology, Syndrome
Pubmed
Web of science
Open Access
Oui
Création de la notice
16/01/2018 14:20
Dernière modification de la notice
08/05/2019 20:27
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