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Kidney Week

Abstract: PO0593

Kidney Targeted Renalase Agonist Peptide Rescues Severe Model of Cisplatin-Induced AKI and CKD

Session Information

  • CKD Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Guo, Xiaojia, Yale University School of Medicine, New Haven, Connecticut, United States
  • Xu, Leyuan, Yale University School of Medicine, New Haven, Connecticut, United States
  • Velazquez, Heino, Yale University School of Medicine, New Haven, Connecticut, United States
  • Chen, Tian-Min, Yale University School of Medicine, New Haven, Connecticut, United States
  • Williams, Ryan, Sloan-Kettering Institute, New York, New York, United States
  • Heller, Daniel A., Sloan-Kettering Institute, New York, New York, United States
  • Safirstein, Robert L., Yale University School of Medicine, New Haven, Connecticut, United States
  • Desir, Gary V., Yale University School of Medicine, New Haven, Connecticut, United States
Background

Cisplatin (CP) causes Chronic Kidney Disease (CKD) upon repeated doses and limits its chemotherapeutic use. Renalase (RNLS) is a protein that activates kinases linked to survival and attenuates acute ischemic and CP-induced kidney injury. We now seek to target delivery of RNLS specifically to kidney to prevent CP-induced CKD.

Methods

CKD was induced in RNLS knockout (KO) (severe) and wild type (WT) mice by 2 doses of CP 15 mg/kg 2 weeks apart. The RNLS agonist peptide RP81 was synthesized and encapsulated in mesoscale nanoparticles (MNP) that target the kidney. Its cytoprotective activity was tested in vitro using TKPTS proximal tubule cells and in vivo using RNLS KO mice. RP81MNP or empty MNP was administered weekly for 4 weeks. Renal injury and function was evaluated by immunohistochemistry and plasma creatinine (Cr). The mechanism of action of RP81MNP was investigated using single cell RNA sequencing (scRNAseq) of whole kidney cells.

Results

MNP were retained intracellularly by TKPTS cells and were localized to proximal tubules in vivo. RP81MNP protected TKPTS cells from CP-induced cytotoxicity: cell viability was enhanced 3.5-fold, n=6, p<.05, compared to empty MNP. Naked RP81 increased cell viability 1.72-fold, n=6, p<.05 over BSA control. Compared to WT, CP in KO caused more severe AKI (Cr: 0.61 mg/dL ± 0.05 vs. 0.13±0.03 in WT, n=3, p<0.05), higher mortality (45% death at 4 weeks n=20, p<0.005), and more severe CKD (Cr 0.16 ± 0.02 mg/dl, vs 0.12 ± 0.01, n=5, p<0.05; ). In KO given CP, RP81MNP ameliorated AKI (Cr 0.30 ± 0.05 mg/dL vs 0.64 ± 0.14 in control, n=5, p<0.05;) and CKD (increased kidney weight: 176mg ± 7.0, vs 145.4± 4.5, decreased plasma Cr: 0.10± 0.01 vs 0.16± 0.02, and KIM-1: 124.3±15.1 pg/ml vs 227±28.4). RP81MMP significantly reduced plasma cytokines IL-1β, IL-2, IL-6, KC, and TNFα and inhibited regulated necrosis. ScRNAseq revealed that RP81MNP preserved tubule and vasculature cell mass and decreased infiltrated immune cells caused by CP.

Conclusion

We conclude that RP81MNP attenuates CP-induced CKD by diminishing cell death pathways and inflammation activated by CP. These data suggest that RP81MNP may be an effective therapeutic agent to prevent CKD in patients treated with repeated doses of cisplatin.

Funding

  • NIDDK Support