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Abstract: FR-PO585

Loss of NCC Impairs the Outgrowth of the Renal Distal Convoluted Tubule (DCT) During Renal Development

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Schnoz, Christina, University of Zurich, Zurich, Switzerland
  • Carrel, Monique, University of Zurich, Zurich, Switzerland
  • Loffing, Johannes, University of Zurich, Zurich, Switzerland
Background

Gitelman syndrome is an autosomal recessive renal tubulopathy characterized by hypokalemic alkalosis, hypomagnesemia and hypocalciuria. The syndrome is caused by loss-of-function mutations in the NaCl co-transporter (NCC) in the renal distal convoluted tubule (DCT). Data from NCC ko mice suggest that DCT atrophy contributes to the pathogenesis of the disease. Since Gitelman patients are usually diagnosed during adolescence or early adulthood, we tested the idea that the late clinical onset of Gitelman syndrome is related to a progressive regression of the DCT during adolescence.

Methods

Immunofluorescent detection of distal tubule marker proteins as well as morphometric analyses of DCT fractional volume and investigation of DCT specific gene expression with real time quantitative PCR were used to analyse the structure and protein expression pattern of the DCT at different ages and stages of development (day 1, 4, 10 and 6 weeks after birth) in NCC wt and NCC ko mice.

Results

Mice of both genotypes developed normal and showed a similar body weight gain. Plasma aldosterone levels and renal renin mRNA expression were higher in NCC ko mice than in NCC wt mice already at day 10. 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 almost similar for mice of both genotypes at day 4, but gets 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 protein abundance of the DCT-specific Mg2+ channel TRPM6 and an increased proteolytic cleavage and hence activation of the alpha- and gamma subunit of the epithelial Na+ channel (ENaC).

Conclusion

Thus, after an initial outgrowth of the DCT up to day 4, DCT development lacks significantly behind in kidneys of NCC deficient mice. The impaired DCT development associates already at day 10 with clear signs of volume contraction with elevated renin and aldosterone levels and an activation of ENaC, suggesting that Gitelman syndrome might be present much earlier during life than usually expected. Despite an early downregulation of TRPM6, hypomagnesemia is a rather late symptom.

Funding

  • Government Support - Non-U.S.