Altered renal distal tubule structure and renal Na(+) and Ca(2+) handling in a mouse model for Gitelman's syndrome.
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.
Loffing
Johannes
J
Department of Pharmacology and Toxicology, University of Lausanne, Rue du Bugnon 27, CH-1005 Lausanne. johannes.loffing@ipharm.unil.ch
Vallon
Volker
V
Loffing-Cueni
Dominique
D
Aregger
Fintan
F
Richter
Kerstin
K
Pietri
Laurence
L
Bloch-Faure
May
M
Hoenderop
Joost G J
JG
Shull
Gary E
GE
Meneton
Pierre
P
Kaissling
Brigitte
B
D000471:Alkalosis / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000502:physiology; D004195:Disease Models, Animal; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism*; D007686:Kidney Tubules, Distal / Q000378:metabolism* / Q000473:pathology*; D008274:Magnesium / Q000378:metabolism*; D051379:Mice; D011955:Receptors, Drug / Q000502:physiology; D012964:Sodium / Q000378:metabolism*; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000502:physiology; D013577:Syndrome
D002352:Carrier Proteins; D011955:Receptors, Drug; C578875:Slc12a3 protein, mouse; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; C064415:thiazide receptor; D012964:Sodium; D008274:Magnesium; D002118:Calcium