Abstract: FR-PO176

Inhibition of Mitochondrial Carnitine Palmitoyl Transferase 1 Prevents Renal Ischemia/Reperfusion Injury in Rats

Session Information

  • Mitochondriacs and More
    November 03, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Damgaard, Mads Vammen, Aarhus University, Aarhus C, Denmark
  • Norregaard, Rikke, Aarhus University, Aarhus C, Denmark
  • Frokiaer, Jorgen, Aarhus University, Aarhus C, Denmark
  • Nielsen, Søren, Aalborg University , Aalborg, Denmark
Background

Acute kidney injury is associated with high mortality and a lack of effective therapeutic treatment of the most common cause i.e., ischemia/reperfusion-injury (IR-I).
Hypoxia leads to ATP depletion, apoptosis and necrosis, resulting in a marked inflammatory cascade causing further tissue damage. Inhibition of the inflammatory responses after IR-I is crucial for renal protection.
Fatty acid β-oxidation is controlled by carnitine palmitoyl transferase 1 (CPT1). Etomoxir (ETO) inhibits CPT1 and block lipid metabolism.
We hypothesize that CPT1 blockade can decrease the inflammatory response, induce an immune modulation, reduce mitochondrial dysfunction and hence alleviate renal IR-I.

Methods

Male Wistar rats (n = 10 animals per group) were subjected to either sham operation or renal ischemia/reperfusion (IR) by bilateral artery clamping for 40 min followed by ETO (5 mg/kg/day) or vehicle administrated at reperfusion. Clearance experiments were performed and renal tissue was removed and prepared for qPCR, immunohistochemistry and western blot analysis at sacrifice 48 hrs after reperfusion.

Results

IR-I resulted in polyuria (ml/kg/day ± SEM, Sham: 36 ± 3, IR: 125 ± 5, IR+ETO: 62 ± 4), increased fractional sodium excretion (%, Sham: 0.3 ± 0.04, IR: 2 ± 0.3, IR+ETO: 0.3 ± 0.09), plasma creatinine (µmol/L/kg, Sham: 77 ± 3, IR: 649 ± 183, IR+ETO: 141 ± 19) as well as BUN (mmol/L/kg, Sham: 18 ± 1, IR: 102 ± 20, IR+ETO: 41 ± 8). ETO treatment prevented these increases, improved creatinine clearance (ml/min, Sham: 7.4 ± 0.6, IR: 1.9 ± 0.2, IR+ETO: 3.8 ± 0.4) as well as attenuated downregulation of AQP1, Na/K-ATPase and AQP2 expression. All changes were significantly different between IR and IR+ETO. In addition, expression of (pro)inflammatory cytokines (IL-6, IL-1β, TNFα, MCP-1, IL-10) and key markers (ICAM-1) were significantly reduced including NGAL (Sham: 1, IR: 49 ± 16, IR+ETO: 1 ± 0.1) and KIM-1 (Sham: 1, IR: 725 ± 101, IR+ETO: 218 ± 65) in response to ETO administration. Expression of CPT1A increased following the ETO treatment (Sham: 1, IR: 1.2 ± 0,1, IR+ETO: 1.6 ± 0.1).

Conclusion

ETO treatment impaired development of renal dysfunction and attenuated tissue injury after renal IR-I. Decreasing the lipid metabolism attenuate the inflammatory response and may provide a novel potent pathway for treatment of renal IR-I.

Funding

  • Government Support - Non-U.S.