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Abstract: PO0380

Dexamethasone Attenuates Kidney Ischemia Reperfusion Injury in SD Rats by Mediating M1 Macrophage Cytokine Production

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Skrypnyk, Nataliya, Janssen Global Services LLC, Titusville, New Jersey, United States
  • Frikke-Schmidt, Henriette, Janssen Global Services LLC, Titusville, New Jersey, United States
  • Frederick, David W., Janssen Global Services LLC, Titusville, New Jersey, United States
  • Albarazanji, Kamal, Janssen Global Services LLC, Titusville, New Jersey, United States
  • Lewis, Gavin, Janssen Global Services LLC, Titusville, New Jersey, United States
  • Liu, Jianying, Janssen Global Services LLC, Titusville, New Jersey, United States
  • Guo, Lili, Janssen Global Services LLC, Titusville, New Jersey, United States
  • Li, Qiu, Janssen Global Services LLC, Titusville, New Jersey, United States
  • Camacho, Raul, Janssen Global Services LLC, Titusville, New Jersey, United States
  • Ma, Li-Jun, Janssen Global Services LLC, Titusville, New Jersey, United States
  • Nawrocki, Andrea R., Janssen Global Services LLC, Titusville, New Jersey, United States
  • Ho, George, Janssen Global Services LLC, Titusville, New Jersey, United States
  • Rankin, Matthew M., Janssen Global Services LLC, Titusville, New Jersey, United States
  • Meng, Rong, Janssen Global Services LLC, Titusville, New Jersey, United States
  • Pocai, Alessandro, Janssen Global Services LLC, Titusville, New Jersey, United States
  • Lee, Seunghun Paul, Janssen Global Services LLC, Titusville, New Jersey, United States
Background

Published evidence suggests a beneficial effect of adjunctive corticosteroid therapy on time of withdrawal from ventilation and time in ICU, as well as a faster reversal of septic shock. Studies in rodent models of acute kidney injury (AKI) have demonstrated a protective role of dexamethasone (Dexa), however its mechanism in attenuation of AKI is not clearly understood. Because M1 macrophages play role in the early stage of sepsis and ischemic kidney injury by producing proinflamatory cytokines contributing to AKI progression, we investigated the effect of Dexa during AKI on M1 polarized macrophages and kidney tubular epithelial cells.

Methods

Bilateral kidney Ischemia Reperfusion (IR) (30 minutes) was performed in 20 male SD rats (n=10/group). Dexa (3mg/kg) was injected IP 30 min before IR. Plasma creatinine, BUN and transcutaneous glomerular filtration rate (tGFR) were evaluated as readout for kidney function. Plasma cytokines were measured at 4 and 24h after IR using a Luminex Multiplex Assay. The human monocytic cell line THP1 was differentiated for 72h after a 4h pulse of 20 ng/mL PMA and then polarized to M1 phenotype in the presence or absence of Dexa. Macrophage-conditioned keratinocyte media was then collected and transferred to HK-2 cells (a human kidney tubular epithelial line) in a hypoxic chamber (0.2% O2) for 48 hrs. Apoptosis of HK-2 cells was evaluated by determining Casp3/7 activity.

Results

Pretreatment of rats with Dexa reduced plasma creatinine (2 vs 1 mg/dL), BUN (121 vs 96 mg/dL) and increased tGFR (0.5 vs 0.8 mL/min) at 24h post IR. Plasma cytokines known to be produced by M1 macrophages such as IL-1β and keratinocyte-derived chemokine (KC) were significantly reduced at 4h while MCP-1 was reduced 4 and 24h after IR. HK-2 cells treated with conditioned media obtained from M1 macrophages in the presence of Dexa and hypoxic conditions showed reduced casp3/7 activity.

Conclusion

Our data demonstrate that Dexa has a renoprotective effect in SD rat with IR-induced AKI. The observed beneficial effect of Dexa seems to involve an indirect anti-apoptotic effect on tubular epithelial cells and potentially a reduction of cytokine production by M1 macrophages.