Loss of sodium chloride co-transporter impairs the outgrowth of the renal distal convoluted tubule during renal development.
Nephrol Dial Transplant
; 35(3): 411-432, 2020 03 01.
Article
em En
| MEDLINE
| ID: mdl-31436795
ABSTRACT
BACKGROUND:
Loss-of-function mutations in the sodium chloride (NaCl) co-transporter (NCC) of the renal distal convoluted tubule (DCT) cause Gitelman syndrome with hypokalemic alkalosis, hypomagnesemia and hypocalciuria. Since Gitelman patients are usually diagnosed around adolescence, we tested the idea that a progressive regression of the DCT explains the late clinical onset of the syndrome.METHODS:
NCC wild-type and knockout (ko) mice were studied at Days 1, 4 and 10 and 6 weeks after birth using blood plasma analysis and morphological and biochemical methods.RESULTS:
Plasma aldosterone levels and renal renin messenger RNA expression were elevated in NCC ko mice during the first days of life. In contrast, plasma ion levels did not differ between genotypes at age 10 days, but a significant hypomagnesemia was observed in NCC ko mice at 6 weeks. Immunofluorescent detection of parvalbumin (an early DCT marker) revealed that the fractional cortical volume of the early DCT is similar for mice of both genotypes at Day 4, but is significantly lower at Day 10 and is almost zero at 6 weeks in NCC ko mice. The DCT atrophy correlates with a marked reduction in the abundance of the DCT-specific Mg2+ channel TRPM6 (transient receptor potential cation channel subfamily M member 6) and an increased proteolytic activation of the epithelial Na+ channel (ENaC).CONCLUSION:
After an initial outgrowth, DCT development lags behind in NCC ko mice. The impaired DCT development associates at Day 1 and Day 10 with elevated renal renin and plasma aldosterone levels and activation of ENaC, respectively, suggesting that Gitelman syndrome might be present much earlier in life than is usually expected. Despite an early downregulation of TRPM6, hypomagnesemia is a rather late symptom.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sódio
/
Síndrome de Bartter
/
Simportadores de Cloreto de Sódio
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Síndrome de Gitelman
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Hiperaldosteronismo
/
Túbulos Renais Distais
/
Magnésio
Tipo de estudo:
Etiology_studies
Limite:
Animals
Idioma:
En
Revista:
Nephrol Dial Transplant
Assunto da revista:
NEFROLOGIA
/
TRANSPLANTE
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Suíça