Kidney Week

Abstract: SA-PO164

Differential Renal Responses to Dexamethasone in Rats and Mice Following AKI

Session Information

• AKI: Mechanisms - III
  November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Frikke-Schmidt, Henriette, Cardiovascular Metabolism Janssen, Spring House, Pennsylvania, United States

Henriette Frikke-Schmidt,

• Beck, Stephen, Cardiovascular Metabolism Janssen, Spring House, Pennsylvania, United States

Stephen Beck,

• Pryor, Meghan Marie, Janssen Research and Development LLC, Spring House, Pennsylvania, United States

Meghan Marie Pryor,

• Meng, Rong, Cardiovascular Metabolism Janssen, Spring House, Pennsylvania, United States

Rong Meng,

• Strizziere, Joseph, Janssen Research and Development LLC, Spring House, Pennsylvania, United States

Joseph Strizziere,

• Rankin, Matthew M., Cardiovascular Metabolism Janssen, Spring House, Pennsylvania, United States

Matthew M. Rankin,

• Guo, Lili, Cardiovascular Metabolism Janssen, Spring House, Pennsylvania, United States

Lili Guo,

• Du, Fuyong, Cardiovascular Metabolism Janssen, Spring House, Pennsylvania, United States

Fuyong Du,

• Patel, Shefali, Janssen Research and Development LLC, Spring House, Pennsylvania, United States

Shefali Patel,

• Nawrocki, Andrea R., Cardiovascular Metabolism Janssen, Spring House, Pennsylvania, United States

Andrea R. Nawrocki,

• Dieleman, Jan M., Westmead Hospital, Westmead, New South Wales, Australia

Jan M. Dieleman,

• de Caestecker, Mark P., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Mark P. de Caestecker,

• Pocai, Alessandro, Cardiovascular Metabolism Janssen, Spring House, Pennsylvania, United States

Alessandro Pocai,

Background

Acute kidney injury (AKI) is a common cause of kidney failure and mortality. No treatments are approved, but the availability of novel diagnostic tools and biomarkers and better understand of human pathogenesis have increased the likelihood of developing an effective therapy. A major missing link to support successful clinical trials in this area is the lack of evidence that efficacy in preclinical models of AKI is translatable into humans. Because there is existing evidence of dexamethasone (dexa) beneficial effect in human (DECS trial) and rodent AKI, dexa was evaluated in ischemia-reperfusion (IR) induced AKI in rats and mice.

Methods

Dexamethasone was administered via IP injection to mice (12 mg/kg) and rats (3 mg/kg) 30 min before kidney ischemia reperfusion (IR). Plasma creatinine (pCre), transcutaneous GFR (tGFR) and kidney gene expression were evaluated 24h after the procedure.

Results

Dexa reduced plasma creatinine, kidney proinflammatory genes (IL-6, CCL2, IL-1β) and increased tGFR on day 1 after IR in rats but not in mice. Consistently, dexa treatment reduced plasma corticosterone levels (translational target engagement (TE) biomarker) only in rats. Kidney mRNA level of glucocorticoid receptor NR3C1 was downregulated in mouse IR but remained unchanged in rat IR. Similar plasma dexa concentrations were detected in rat and mice.

Conclusion

While the interpretation of these data is limited by the lack of availability of TE and plasma exposures in the DECS clinical trial, the differential responses observed in rat and mice may be attributed to downregulation of steroid receptor expression in mouse kidneys. Appropriate omics characterization together with translational biomarkers and compound exposures in humans and animals may provide significant insights and increase preclinical model translatability in AKI.

Funding

• Commercial Support – Janssen