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Kidney Week

Abstract: FR-PO148

Nrf2/Keap1 Pathway Activation Improves Kidney Injury in Nephrotoxic AKI in Mice

Session Information

  • AKI: Mechanisms - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Liu, Jianying, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Du, Fuyong, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Camacho, Raul, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • D'Aquino, Katharine, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Guo, Lili, Johnson & Johnson Services Inc, New Brunswick, New Jersey, United States
  • Meng, Rong, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Pocai, Alessandro, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Nawrocki, Andrea R., Janssen Research and Development LLC, Spring House, Pennsylvania, United States

Group or Team Name

  • CVMR-PH Research, Janssen Research & Development LLC.
Background

Acute kidney injury (AKI) is highly prevalent and increases the risk of chronic kidney disease without treatment options. Preclinical evidence shows that regulating nuclear factor erythroid 2–related factor (Nrf2/Keap1) pathways attenuate AKI by increasing expression of anti-oxidant and anti-inflammatory genes including peroxisome proliferator-activated receptor-γ, and heme oxygenase1. To establish an AKI model to investigate the Nrf2/Keap1 pathway, we used the Nrf2 activator CDDO-Imidazolide (CDDO-IM) to benchmark its effects in cisplatin (Sic) nephrotoxicity, cecal slurry (CS) sepsis, and ischemia reperfusion (IRI) induced AKI models in mice.

Methods

The Cis-AKI model was induced by 20 mg/kg cis in C57 mice. The CS sepsis-AKI was caused by a single dose of 450 ul of CS. The IRI-AKI was induced by bi-clamping of mouse renal pedicles for 26 min. The mice were treated with CDDO-IM (10 mg/kg, PO) prior to AKI induction. Renal function was evaluated by plasma creatinine (pCr) and expression of Nrf2 target genes (Nqo1/Txnrd1), tubular injury markers (KIM1/NGAL). Acute tubular necrosis was evaluated and scored.

Results

In the cisplatin model pCr levels increased from d1 through d4 indicating acute kidney injury. Pre-treatment of mice with CDDO-IM significantly reduced the pCr levels through d4 (pCr 0.32±0.047 in CDDO-IM vs. Vehicle 0.98±0.23 mg/dl; p<0.001). Txnrd1 was upregulated while kidney injury markers KIM1 and NGAL were downregulated. Furthermore, tubular necrosis was reduced indicating CDDO-IM prevented tubular injury and improved recovery from AKI. Unexpectedly, pre-treatment with CDDO-IM did not attenuate kidney injury in the CS or IRI model despite clear enhancement of NRF2 target expression. In contrast, Dexamethasone significantly improved renal function in sepsis and IRI mouse models of AKI.

Conclusion

The protective effect of Nrf2 activator CDDO-IM was evaluated in commonly used AKI models. CDDO-IM pretreatment significantly attenuated plasma biomarkers and tubular necrosis in cis, but not in sepsis or IRI related AKI in mice. The reasons for the model differences are unclear but could be related to the timing of Nrf2 activation in relation to the induction and disease progression, the severity of injury and potentially altered kidney exposures due to AKI.

Funding

  • Commercial Support – J & J Janssen parmaceutical