Loss of sodium chloride co-transporter impairs the outgrowth of the renal distal convoluted tubule during renal development
Open Access
- 22 August 2019
- journal article
- research article
- Published by Oxford University Press (OUP) in Nephrology Dialysis Transplantation
- Vol. 35 (3), 411-432
- https://doi.org/10.1093/ndt/gfz172
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.Keywords
Funding Information
- University of Zurich
- Swiss National Centre for Competence in Research ‘Kidney
- Swiss National Science Foundation (310030_173276/1)
This publication has 25 references indexed in Scilit:
- Early appearance of hypokalemia in Gitelman syndromePediatric Nephrology, 2010
- Hypokalaemia and failure to thrive: report of a misleading onsetJournal of Paediatrics and Child Health, 2010
- Thiazide Effects and Adverse EffectsHypertension, 2009
- Gitelman syndromeOrphanet Journal of Rare Diseases, 2008
- Hypokalemia in a mouse model of Gitelman's syndromeAmerican Journal of Physiology-Renal Physiology, 2006
- Altered Renal Distal Tubule Structure and Renal Na+ and Ca2+ Handling in a Mouse Model for Gitelman’s SyndromeJournal of the American Society of Nephrology, 2004
- Thiazide treatment of rats provokes apoptosis in distal tubule cellsKidney International, 1996
- Gitelman's variant of Barter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na–Cl cotransporterNature Genetics, 1996
- Mechanism of calcium transport stimulated by chlorothiazide in mouse distal convoluted tubule cells.JCI Insight, 1992
- Thiazide treatment of systemic hypertension: Effects on serum magnesium and ventricular ectopic activityThe American Journal of Cardiology, 1989