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Kidney Week

Abstract: TH-PO461

Proximal Tubule Activation of B-Catenin Ameliorates Chronic Kidney Injury in Mice

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Nlandu khodo, Stellor, University of Zurich, Zurich, Switzerland
  • Tonello, Jane Marie, Vanderbilt Medical Center, Nashville, Tennessee, United States
  • Phillips Mignemi, Melanie, Vanderbilt Medical Center, Nashville, Tennessee, United States
  • Gewin, Leslie S., Vanderbilt University, Nashville, Tennessee, United States
Background

Tubulointerstitial fibrosis (TIF) is the hallmark of chronic kidney disease (CKD), and growth factors play an important role in injury and TIF. The Wnt/b-catenin pathway has been shown to be protective in acute kidney injury (AKI), but is thought to promote CKD progression, likely mediated by b-catenin signaling in mesenchymal cells. However, the cell-autonomous effects of b-catenin signaling on chronically injured tubules remains unknown.

Methods

To address how proximal tubule (PT)-specific b-catenin alters the response to chronic injury, we generated conditional mice with constitutive activation of b-catenin in the PT (gGT-Cre;Ctnnb1ex3fl/fl). We injured these mice and their floxed littermates using two models of AKI to CKD: aristolochic acid nephropathy (AAN) and ischemia reperfusion (IRI) plus delayed contralateral nephrectomy. We used murine PT cells for in vitro studies.

Results

Surprisingly, 6 weeks after AAN, injury score, KIM-1 transcript, cortical fibrosis and BUN levels were decreased in conditional mice compared to their controls, suggesting that b-catenin signaling in the PT is protective. Cortical tubular apoptosis was decreased in the conditional mice. Consistently, stabilizing b-catenin in vitro (Wnt3a or GSK-3 inhibitor) also reduced aristolochic acid (AA)-induced apoptosis. Oxidative stress reportedly switches b-catenin transcriptional binding partners from LEF/TCF to FoxO, but this has not been examined in PT cells. We found that oxidative stress, present in CKD, reduced LEF/TCF-dependent transcription in PT cells (Topflash and Axin2 mRNA) and augmented FoxO3 activity. Co-IP studies showed that oxidative stress plus Wnt3a significantly increases nuclear FoxO3/b-catenin interactions. In the AAN model, injured conditional b-catenin mice have augmented nuclear FoxO3 expression in proximal tubules. Furthermore, FoxO3 was required for b-catenin’s protective effect as mice with PT-specific b-catenin stabilization and FoxO3 deletion (using gGT-Cre) lost the protective effect in AAN. RNAseq on PT cells was performed and identified 19 novel b-catenin and FoxO3 targets.

Conclusion

In conclusion, b-catenin signaling within the proximal tubule mitigates AKI to CKD transition through its interaction with FoxO3. Ongoing efforts are examining this b-catenin effect in the IRI and validating novel targets in vivo.

Funding

  • Veterans Affairs Support