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Abstract: SA-PO070

Phenotype of Ksp-Cadherin Deficient Mice: Enhanced Recovery from AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

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
  • 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
  • Kakade, Vijayakumar R., Yale University School of Medicine, New Haven, Connecticut, United States
  • Marlier, Arnaud, Yale University School of Medicine, New Haven, Connecticut, United States
  • Knauf, Felix, University Hospital Charite Berlin, Berlin, Germany
  • Jagels, Lea, Friedrich-Alexander-Universität Erlangen-Nürnberg, Hamburg, Germany
  • Lück, Anja, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
  • Cantley, Lloyd G., Yale University School of Medicine, New Haven, Connecticut, United States
  • Aronson, Peter S., Yale University School of Medicine, New Haven, Connecticut, United States
Background

We have generated a mouse line that is deficient in Ksp-cadherin (Ksp-null), a member of the cadherin superfamily of cell adhesion molecules that is primarily expressed on the basolateral membrane of renal tubular epithelial cells (Thomson et al. ASN 2019). To further elucidate the phenotype of this null-mutation, we exposed Ksp-null and wild-type (WT) mice to an aristolochic acid (AA)-based model of AKI.

Methods

A single application of AA (2 mg/kg body weight) or vehicle alone was administered by i.p. injection to 10 week-old Ksp-null and WT male mice.

Results

At one week post AA exposure both cohorts showed similar levels of renal injury by histological evaluation. BUN values rose to 74 and 79 mg/dL for Ksp-null and WT animals respectively and serum creatinine values rose to 0.473 and 0.632 mg/dL respectively. Three weeks post AA treatment, WT animals had persistently elevated BUN and serum creatinine values of 80 and 0.462 mg/dL respectively and substantial evidence of unresolved tubular injury. In contrast, the Ksp-null animals had significantly lower BUN and serum creatinine values (35 and 0.206 mg/dL respectively) and histological evaluation revealed that their tubular injury had largely resolved. To gain insight into the nature of this accelerated recovery, we performed a comparative evaluation of kidneys from Ksp-null and WT animals specifically looking for differences in cell proliferation indices, inflammatory cytokine expression levels, immune cell response, and Klotho expression levels. No differences were observed between Ksp-null and WT animals at 1 week post AA injection. At 3 weeks post AA injection, however, Ksp-null animals exhibited significantly lower levels of expression of CD68, TGF-β, p16INK4a, IL-6, and Arg1. Furthermore, Ksp-null kidneys demonstrated significantly higher levels of Ki67 staining and significantly enhanced recovery of Klotho expression.

Conclusion

In conclusion, despite sustaining similar levels of initial injury in response to AA exposure, Ksp-null animals exhibited an accelerated recovery relative to WT controls that was characterized by enhanced cell proliferation, elevated levels of Klotho, lack of persistent expression of immune cells, and decreased expression of inflammatory cytokines.

Funding

  • NIDDK Support