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Kidney Week

Abstract: SU-OR11

Inhibition of Cadherin 11 Improves Outcomes in Murine Models of CKD

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Huffstater, Tessa, Vanderbilt University, Nashville, Tennessee, United States
  • Raddatz, Michael A., Vanderbilt University, Nashville, Tennessee, United States
  • Gewin, Leslie S., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Merryman, W. David, Vanderbilt University, Nashville, Tennessee, United States
Background

Chronic kidney disease (CKD) represents a massive unmet clinical need, as there are virtually no pharmaceutical options for treatment of renal injury. A recent study identified cadherin-11 (CDH11) as a potential biomarker for CKD, as it is present in kidney biopsies and urine samples of CKD patients and its expression is increased in CKD mouse models. We have investigated the role of CDH11 as both a mediator and therapeutic target of CKD.

Methods

In the current study, we used three mouse models of CKD to evaluate the role of CDH11: aristolochic acid nephropathy, unilateral ureteral obstruction, and uninephrectomy/angiotensin II administration. In each of these models, we inhibited CDH11 genetically using transgenic mice and pharmacologically with the administration of a functional blocking antibody to CDH11.

Results

Although CDH11 has been found on immune cells and fibroblasts in other fibrotic diseases, we found that in the kidney CDH11 is exclusively expressed in injured proximal tubules (PTs). PTs play a significant role in CKD, as they are both a target and mediator of chronic injury. In our models of CKD, we found that both genetic and pharmacologic CDH11 inhibition improves renal function (BUN and ACR), diminishes cytokine production (TGF-β1 and IL-6 expression), and reduces tubular injury (expression of KIM-1 and histological analysis). Using primary PT cells, we found that genetic ablation of CDH11 improves cell survival in vitro. Although the specific mechanism by which CDH11 mitigates PT injury is still under investigation, preliminary data shows that inhibition of CDH11 increases Wnt/β-catenin activity in the kidneys of injured mice. Wnt/β-catenin signaling promotes cell survival, which in this context could result in reduced tubular atrophy, cytokine production, and fibrosis. Such pro-survival signaling could be driving the reduction in renal injury we see when CDH11 is inhibited, as PT death strongly correlates with outcomes in CKD.

Conclusion

These results clearly identify CDH11 inhibition as a novel means of improving outcomes in murine CKD models. The mechanism by which CDH11 inhibition mitigates renal injury is likely through CDH11 interactions with the Wnt/β-catenin signaling pathway to enhance PT survival. These results could prove an important step towards developing new therapeutic strategies for the treatment of CKD.

Funding

  • Other NIH Support