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Kidney Week

Abstract: FR-PO953

Porcupine in the Kidney Protects Against Nephrotoxic Serum Nephritis by Inhibiting Innate Immune Signals

Session Information

  • CKD: Pathobiology - I
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Lu, Xiaohan, Duke University, Durham, North Carolina, United States
  • Ren, Jiafa, Duke University, Durham, North Carolina, United States
  • Wen, Yi, Duke University, Durham, North Carolina, United States
  • Yang, Ting, Duke University, Durham, North Carolina, United States
  • Crowley, Steven D., Duke University, Durham, North Carolina, United States

Group or Team Name

  • Crowley Lab
Background

10% of the world’s population suffers from chronic kidney disease (CKD), and glomerulonephritis is a prominent cause of CKD. Wnt/β-catenin signaling can protect the renal tubule by modulating apoptosis and survival pathways. All 19 Wnt ligand isoforms must undergo porcupine (PORCN)-dependent Wnt O-acylation to be secreted. Therefore, we hypothesized that PORCN could mitigate CKD by driving Wnt secretion in the nephron.

Methods

To examine the role of tubular PORCN in CKD, we bred 129/SvEv PORCNflox/flox mice with the Pax8-rtTA and Tet-On lines to generate inducible renal epithelial cell PORCN knockout mice (PORCN iKKO). Mice with all 3 transgenes were used as the PORCN iKKO group, whereas mice lacking Pax8-rtTA or Tet-On transgene acted as wild-type (WT) controls. After 14 days of nephrotoxic serum nephritis (NTS), kidney injury was assessed by BUN, renal pathology, and kidney mRNA levels of injury/fibrosis biomarkers. The expression of cytokines and other innate immune signaling components was determined by real-time PCR. A TNFα antagonist (R7050, 12mg/body weight) was administered by intraperitoneal injection every other day during NTS.

Results

At baseline, mRNA levels for PORCN are reduced by 88% in the PORCN iKKO kidneys compared to WT littermates with preserved PORCN expression in other tissues. On day 14 of NTS, PORCN iKKO mice exhibited higher BUNs (202 ± 12 vs. 101 ± 38, mg/dL; p<0.01), and renal mRNA levels for NGAL (6.1±1.14 vs 1.0±0.35 au, p=0.0013), KIM-1(2.5±0.65 vs 1.0±0.26 au, p=0.046), collagen I (2.4±0.31 vs 1.0±0.38 au, p=0.025), and fibronectin (2.5±0.35 vs 1.0±0.27 au, p=0.006) compared to WTs. Renal protein levels for collagen I and fibronectin recapitulated the mRNA patterns. In the diseased kidneys, PORCN iKKO had a higher cytokine mRNA level for TNFα (2.6±0.67 vs. 1.0±0.30 au, p=0.036) than WTs at day 14 NTS. In addition, mRNAs for CD74 (2.7±0.53 vs. 1.0±0.44 au, p=0.038) and OPN (3.6±0.68 vs. 1.0±0.49 au, p=0.012), which are linked in a signaling network that lies downstream of Wnt/b-catenin were significantly increased in PORCN iKKO kidneys during NTS. Blockade of TNFα signaling blunted the exaggerated kidney injury in PORCN iKKO mice.

Conclusion

PORCN in the kidney limits autoimmune nephritis severity, suggesting that activation of PORCN-dependent Wnt/β-catenin signaling in the renal tubule may ameliorate CKD.

Funding

  • NIDDK Support