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Abstract: FR-PO121

Renalase Protects Renal Injury by Maintaining Mitochondrial Dynamic Homeostasis

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    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
  • Moeckel, Gilbert W., 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 participates in the salvage pathway for intracellular NADH. When secreted, it signals through the calcium ATPase ATP2b4 and activates kinases linked to survival. RNLS attenuates acute ischemic and cisplatin (CP)-induced kidney injury. We aim to elucidate the function of RNLS in renal mitochondrial homeostasis.

Methods

RNLS knockout (KO) and wild type (WT) mice were given CP at 15 mg/kg or vehicle control for 4 days and kidneys were collected and analyzed for structure with electron microscopy (EM), mitochondrial proteins with immunoblotting, and mitochondrial respiration assayed ex-vivo.

Results

CP induced severe renal damage in RNLS deficient animals as evidenced by plasma creatinine: KO 1.178 ± 0.285 mg/dL, n=13 vs WT 0.151 ± 0.026 mg/dL, n=14, p<0.005). EM analysis revealed that RNLS KO kidneys had 30% more mitochondria compared to control WT, while in CP treated animals, there was no difference in number of mitochondria between the strains. CP treatment induced 4-fold increase in autophagosomes in RNLS KO mice and only 2-fold increase in WT animals. Parkin protein, which plays a key role in mitophagy and mitochondrial motility and size, was not detected in WT control kidneys but was expressed in RNLS KO mouse kidneys. CP induced Parkin in WT and dramatically enhanced Parkin level in KO. AMPKα and AMPKβ were highly activated, and OPA-1 was reduced in RNLS KO AKI as compared to WT AKI kidneys. 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 the impaired mitochondrial activities of complexes I and II in RNLS KO kidneys (n=3, p<0.001).

Conclusion

Knockout of RNLS alters mitochondrial dynamics, and CP augmented mitophagy and autophagy during AKI as compared to WT-AKI. Recombinant RNLS attenuates mitochondrial dysfunction in vitro. These data suggest that renalase may be an effective therapeutic agent for mitochondrial relevant disorders, such as cisplatin-induced kidney injury and neurodegeneration.

Funding

  • Other NIH Support