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Abstract: FR-PO076

Lactate Improves Survival in Mice with Sepsis Through HCA2 Activation

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Takakura, Ayumi, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Zandi-Nejad, Kambiz, BIDMC/HVMA-Harvard Medical School, Boston, Massachusetts, United States
Background

Sepsis is characterized by systemic inflammation due to infection and is the most common cause of acute kidney injury (AKI) in critically ill patients. During sepsis, activation of pro-inflammatory pathways results in dysfunction of mitochondria and cells, leading to multi-organ failure.

Methods

Wild-type and Hca2-/- mice were undergone cecal ligation and puncture (CLP) to induce sepsis. For survival study, we monitored the mice for 2 weeks after CLP. For treatment study, we administered either normal saline or lactated Ringer’s solution once a day for total of 3 injections. The isolated peritoneal fluid or cells were subjected to ELISA assay and real time RT-PCR analyses.

Results

Here we show that: 1) in peritoneal immune cells from mice undergone cecal ligation and puncture (CLP), hydroxycarboxylic acid receptor 2 (HCA2) expression increased in parallel with pro-inflammatory cytokines; 2) survival rates for Hca2-/-mice after CLP were lower than for wild-type mice (~40% vs. ~80%) 2 weeks after CLP-induced sepsis, suggestive of a protective role for HCA2 in sepsis; 3) early mortality of Hca2-/-mice were associated with higher pro-inflammatory cytokine production in Hca2-/-peritoneal fluid compared to wild-type; 4) administration of lactated Ringer's (LR) has beneficial effects on mortality in wild-type mice (but not Hca2-/-mice) during sepsis; 5) unlike normal kidneys, kidneys in the setting of sepsis expressed Hca2; 6) LR administration attenuated sepsis-associated AKI, partly restored expression of the key regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator-1-a(PGC1a), and reduced pro-inflammatory cytokine production. Our data suggest that lactate-induced activation of HCA2 regulates a negative feedback loop during sepsis to decrease the inflammatory response.

Conclusion

The data further suggest that fluid resuscitation with LR solution may benefit patients with sepsis, particularly those with sepsis-associated AKI treated with potentially lactate-depleting renal replacement therapies (RRT).

Funding

  • Clinical Revenue Support