Abstract: TH-PO243

Modulation of PPARδ with MTB-2 Post-Reperfusion Attenuates IR-Induced AKI Injury Biomarkers and Histopathology in Rats

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Bracken, Christina, Mitobridge, Cambridge, Massachusetts, United States
  • Pulito, Katelyn, Mitobridge, Cambridge, Massachusetts, United States
  • Tozzo, Effie, Mitobridge, Cambridge, Massachusetts, United States
Background

Ischemic acute kidney injury (AKI) is characterized by persistent proximal tubule mitochondrial dysfunction. Due to their highly oxidative metabolism, proximal tubule cells utilize fatty acids to generate the energy required for their specialized function. We hypothesized that enhancing fatty acid oxidation with a PPARδ modulator will restore mitochondrial function, offering a potential therapeutic treatment for AKI.

Methods

Sprague-Dawley (SD) rats underwent a 45 minute bilateral ischemia-reperfusion (IR) AKI. Following reperfusion rats were treated with 2 IV doses of selective PPARδ modulator MTB-2 at doses varying from 0.3 to 10 mg/kg or vehicle. Plasma and urinary kidney injury biomarkers were measured at 10h, 24h and 48h post reperfusion. Histology assessment of kidney cortex was done 48h post AKI.

Results

MTB-2 treatment resulted in significantly lower plasma creatinine (up to 69% reduction), BUN (up to 60% reduction) and cystatin C (up to 69% reduction) levels at 24 and 48 hours post AKI compared to vehicle animals. Importantly, this translated to an improvement of renal function marked by increased creatinine clearance (up to 800%) and normalization of fractional excretion of Na+ (FENa) (up to 90%) suggesting improved tubular function. Modulation of PPARδ after AKI also led to significantly reduced urinary levels of [TIMP-2]*[IGFBP-7], FABP-1 and NGAL. Assessment of kidney histopathology at 48 hours post reperfusion confirmed that MTB-2 reduced tubular injury and normalized renal tubular architecture, resulting in improvement of histopathology scores.

Conclusion

Our data demonstrates that selective PPARδ modulation after an ischemic AKI event in rats is sufficient to recover renal and tubular function, reduce clinically relevant urinary and plasma injury biomarkers and improve kidney histopathology.