ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: SA-OR59

Inhibition of Cadherin-11 Ameliorates Kidney Injury via Restored Expression of Alpha-1 Antitrypsin

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
  • Riley, Lance 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 the pharmaceutical options for treatment of renal injury are extremely limited. A recent study identified cadherin-11 (CDH11) as a potential biomarker for CKD. CDH11 is present in kidney biopsies and urine samples of CKD patients, and its expression is increased in CKD mouse models, but it’s unclear whether it mediates CKD and could be a target for therapy.

Methods

We used three mouse models of CKD to evaluate the role of CDH11: aristolochic acid nephropathy (AAN), unilateral ureteral obstruction (UUO), and uninephrectomy/angiotensin II administration (Unx/AngII). In each of these models, we inhibited CDH11 genetically using transgenic mice and pharmacologically with the administration of a functional blocking antibody to CDH11. We also used de-identified electronic medical records (IRB 211049) to verify the clinical relevance of the proposed mechanism whereby CDH11 knockout improves kidney injury.

Results

We found that CDH11 is exclusively expressed in injured murine proximal tubules (PTs). PTs play a critical role in CKD, as they are both a target and mediator of chronic injury. In models of CKD, both genetic and pharmacologic CDH11 inhibition improves renal function (BUN and proteinuria), diminishes cytokine production (TGF-β1 and IL-6 expression), and reduces tubular injury (KIM-1 and histological analysis). RNAseq from AAN- and Unx/AngII-injured kidneys revealed that CDH11 knockout mice had significantly increased expression of alpha-1 antitrypsin (A1AT) compared to wild type controls. Additionally, siRNA knockdown of CDH11 in immortalized PT cells in vitro results in elevated expression of A1AT, confirming this mechanistic link. The protease inhibitor A1AT has been shown by others to promote PT survival in several kidney injury models. Using Cox proportional hazards models, we discovered that patients with A1AT mutations have increased incidence of CKD on a per-allele basis, with hazard ratios as high as 5.35.

Conclusion

These results identify CDH11 inhibition as a novel means of improving outcomes in murine CKD models and suggest an underlying mechanism of increased A1AT expression and enhanced PT survival. These findings advance our understanding of CKD and outline a potential new therapeutic strategy.

Funding

  • NIDDK Support