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Kidney Week

Abstract: FR-PO612

Phenotype of Ksp-Cadherin Deficient Mice: Normal Kidney Development but Delayed Maturation of Maximal Urinary Concentrating Ability

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Thomson, Robert Brent, Yale University School of Medicine, New Haven, Connecticut, United States
  • Dynia, Diane W., Yale University School of Medicine, New Haven, Connecticut, United States
  • Burlein, Sarah, Yale University School of Medicine, New Haven, Connecticut, United States
  • Thomson, Benjamin R., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Booth, Carmen Jane, Yale University School of Medicine, New Haven, Connecticut, United States
  • Knauf, Felix, University Hospital Charite Berlin, Berlin, Germany
  • Wang, Tong, Yale University School of Medicine, New Haven, Connecticut, United States
  • Aronson, Peter S., Yale University School of Medicine, New Haven, Connecticut, United States
Background

Ksp-cadherin is a largely kidney-specific member of the cadherin superfamily of cell adhesion molecules. Despite ubiquitous basolateral expression throughout the tubular nephron its function remains unknown.

Methods

To address this question we have generated Ksp-cadherin deficient mice (Ksp-null) by introducing a premature stop codon into the second exon of the Ksp-cadherin gene.

Results

Homozygous Ksp-null animals were born at expected frequencies and were not overtly different from age- and gender-matched wild-type (WT) controls. Kidneys from neonate and adult Ksp-null and WT mice had no discernible differences in the ultrastructural organization of nephrogenic progenitors or mature nephrons. Analysis of E-cadherin and Na/K-ATPase indicate that E-cadherin expression is not modified to compensate for Ksp-cadherin loss and that epithelial cell polarity is unaffected. Serum electrolytes, total CO2, BUN, and creatinine levels were not significantly different between the two groups. Under basal conditions 10 week-old Ksp-null animals produced a urine that was significantly less concentrated than that from a matching WT cohort (1463 ± 219 vs 2184 ± 164 mOsm respectively; P=0.0249). After 24 hrs of water deprivation, similarly aged Ksp-null animals were unable to concentrate their urine to the same extent as their WT counterparts (3283 ± 69 vs 3840 ± 112 mOsm respectively; P=0.0017). Expression analysis of NKCC2, UTA1-3, UTB, AQP1+2, V2R, ROMK, CLCK1, and UMOD indicated that the concentrating defect was not due to altered expression of the principal proteins involved in the generation of the cortico-medullary osmotic gradient. Immunolocalization studies suggested that the defect may be due to misexpression of AQP2 in the IMCD of the Ksp-null mutants. Under both baseline and water-restricted conditions 10 month-old Ksp-null mutants were able to concentrate their urine to the same extent as similarly aged WT animals, suggesting that the defect in urinary concentrating ability in the 10 week-old Ksp-null mice is due to a developmental delay.

Conclusion

In conclusion Ksp-cadherin is not essential for nephron formation or nephron segment delineation. Its null mutation does, however, significantly delay the maturation of maximal urinary concentrating ability.

Funding

  • NIDDK Support