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Kidney Week

Abstract: TH-PO099

Renalase Ameliorates AKI by Altering Mitochondrial Function to Induce Cellular Repair Mechanisms

Session Information

  • AKI: Mechanisms - I
    November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Guo, Xiaojia, Yale School of Medicine, New Haven, Connecticut, United States
  • Chen, Rongmin, Yale School of Medicine, New Haven, Connecticut, United States
  • Chen, Tian-Min, Yale School of Medicine, New Haven, Connecticut, United States
  • Safirstein, Robert L., Yale School of Medicine, New Haven, Connecticut, United States
  • Jonas, Elizabeth A., Yale School of Medicine, New Haven, Connecticut, United States
  • Desir, Gary V., Yale School of Medicine, New Haven, Connecticut, United States
Background

Renalase (RNLS) is a protein that activates kinases linked to survival and attenuates acute ischemic and cisplatin (CP)-induced kidney injury. We now study RNLS role in inducing changes in mitochondrial function to assist in survival and repair of injured tissue.

Methods

RNLS knockout (KO) and wild type (WT) mice were given CP at 15 mg/kg or vehicle control. Kidney mitochondrial structure was analyzed by electron microscopy (EM), and mitochondrial proteins were analyzed by immunoblotting, co-immunoprecipitation and patch clamp recording. The activities of complex I and II were evaluated in mitochondria isolated from kidneys of WT and KO with and without CP.

Results

Both RNLS and its receptor PMCA4b were detected in WT mitochondria by immunofluorescence and RNLS was localized to the inner mitochondrial membrane or matrix by pan-Expansion Microscopy. CP induced severe renal damage in RNLS deficient animals as evidenced by a 7.8-fold increase in plasma creatinine (KO 1.18 ± 0.29 mg/dL, n=13 vs WT 0.15 ± 0.03 mg/dL, n=14, p<0.005). By EM, WT kidney demonstrated decreased mitochondrial area (suggesting fission) and osmotic changes; in contrast mitochondria in RNLS KO were deficient in these activities. Cisplatin induced increased markers of mitophagy and stress in KO vs. WT; Parkin, p-AMPKα and p-AMPKβ were increased, OPA-1 expression was decreased. RNLS KO mouse kidneys exhibited reduced mitochondrial complex I and II activities as compared to WT (p<0.005 and p<0.05, respectively, n=5); recombinant RNLS rescued these activities in RNLS KO kidneys (n=3, p<0.001). Physiological recording of mitochondrial inner membranes of KO and WT animals showed that RNLS addition increased the conductance of the mitochondrial inner membrane.

Conclusion

RNLS alters mitochondrial morphology and function in response to renal injury. The absence of RNLS increases mitophagy, possibly in lieu of metabolic repair mechanisms during CP-AKI. These data suggest that RNLS modifies renal injury by encouraging metabolic repair mechanisms as opposed to mitochondrial removal via mitophagy.