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Abstract: FR-OR11

Intracellular Magnesium Trafficking: A Novel Target to Prevent Ischemic Kidney Injury

Session Information

  • AKI Research: Mechanisms
    November 04, 2022 | Location: W230, Orange County Convention Center‚ West Building
    Abstract Time: 04:30 PM - 04:39 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Reeves, William Brian, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States
  • Wang, Weiwei, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States
  • Li, Kang, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States
  • Kim, Serena Jiyeon, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States
  • Venkatesan, Manigandan, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States
  • Vishnu, Neelanjan, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States
  • Ramachandran, Karthik, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States
  • Madesh, Muniswamy, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States
Background

Mitochondrial dysfunction is a hallmark of AKI. We recently reported that intracellular lactate triggers the release of Mg2+ from endoplasmic reticulum with subsequent Mg2+uptake by mitochondria via the mitochondrial Mg2+ channel Mrs2 (Daw et al Cell 2020). High mitochondrial Mg2+ uptake resulted in impaired mitochondrial function. Since lactate accumulation occurs in conditions of impaired oxidative phosphorylation, we explored the role of mitochondrial Mg2+ uptake in ischemic AKI.

Methods

We induced ischemic AKI via bilateral clamping of the renal pedicle for 26 minutes in male WT mice and in mice lacking Mrs2 (Mrs2 KO). Kidney function was assessed by measurement of blood urea nitrogen (BUN) and creatinine. Kidney histology was assessed by PAS staining and Ly6G staining for neutrophils.

Results

WT mice developed severe loss of renal function (24 hr BUN=99+16 mg/dl, Cr= 1.13+.19 mg/dl, n=9), along with elevated KIM1 and NGAL, histologic tubular injury and leukocyte infiltration. In contrast, Mrs2 KO mice had preserved renal function (BUN=27+7 mg/dl, creatinine=0.48+0.09 mg/dl, n=9, P<0.01 vs WT) and less histologic damage and inflammation. Studies in bone marrow chimeric mice demonstrated that the presence or absence of parenchymal Mrs2, rather than hematopoietic Mrs2, accounted for these differences. CPACC, a novel inhibitor of Mrs2, administered 2 hours prior to ischemia largely prevented ischemic kidney injury (Cr: CPACC 0.35+0.06 mg/dl vs saline 1.47+0.30, P=0.006, n=5). To explore the potential role of lactate in mediating these effects, we administered oxamate, an inhibitor of LDH, which catalyzes the conversion of pyruvate to lactate, prior to ischemia. Mice which received oxamate, sustained significantly less renal dysfunction (BUN 34+5 mg/dl; Cr 0.37+.06 mg/dl), histologic injury and inflammation than saline treated mice (BUN 148+25 mg/dl, Cr 0.93+0.12 mg/dl, P=0.0001). Administration of oxamate 6 hours after ischemia had no protective effect.

Conclusion

These results support the view that lactate-triggered Mg2+ uptake into mitochondria is a critical mediator of ischemic AKI and that targeting this pathway may prevent ischemic kidney injury.

Funding

  • NIDDK Support