Abstract: FR-PO092

MA-0204 Modulation of PPARδ Promotes Recovery after AKI in Normal and Aged Proteinuric Diabetic CKD Zsf1 Rats by Enhancing Fatty Acid Oxidation in Proximal Tubular Epithelial Cells

Session Information

  • AKI Clinical: Predictors
    November 03, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Acute Kidney Injury

  • 001 AKI: Basic


  • Bracken, Christina, Mitobridge, Cambridge, Alabama, United States
  • Pulito, Katelyn, Mitobridge, Cambridge, Alabama, United States
  • Stanwix, Jeff H, Mitobridge, Cambridge, Alabama, United States
  • Hoang, Hien G, Mitobridge, Cambridge, Alabama, United States
  • Campos-bilderback, Silvia B., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Sandoval, Ruben M., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Molitoris, Bruce A., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Tozzo, Effie, Mitobridge, Cambridge, Alabama, United States

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 (FAO) with a PPARδ modulator will restore mitochondrial function and offer a potential therapeutic treatment for AKI.


Human hTERT RPTECs were treated with MA-0204 and analyzed for PPARδ target gene expression and their ability to utilize palmitate. Sprague-Dawley (SD) rats underwent ischemia-reperfusion (IR) AKI and were treated orally with 30 mg/kg of selective PPARδ modulator MA-0204 for 2 days. EPO served as positive control and was dosed IV at 1000 U/kg 30 minutes prior to ischemia. We also tested this hypothesis in aged (18 week old), diabetic and proteinuric CKD Zsf1 rats, a preclinical model that presents with similar comorbidities as diabetic-chronic kidney disease (CKD) patients.


MA-0204 significantly increased expression of PPARδ-target genes associated with mitochondrial FAO (such as Cpt1a) and increased palmitate oxidation in RPTECs. In rats, MA-0204 treatment significantly reduced plasma creatinine (69%), BUN (62%), fractional excretion of Na+ (82%) and restored creatinine clearance (800%) 24 and 48 hours post AKI. MA-0204 treated rats had significantly improved histopathology scores, normalized expression of kidney injury related genes (KIM-1, NGAL), and reduced urinary injury biomarker levels ([TIMP2]*[IGFBP7], FABP-1). Importantly MA-0204 attenuated AKI in diabetic proteinuric CKD Zsf1 rats, resulted in a decrease of plasma creatinine levels (33%), accelerated recovery of creatinine clearance and reduced urinary TNFR1, an indicator of CKD progression.


Our data demonstrates that enhancing fatty acid oxidation and improving mitochondrial function, through PPARδ modulation, following ischemic kidney injury is sufficient to recover renal function, reduce tubular injury and promote recovery in SD as well as in aged, diabetic, proteinuric CKD Zsf1 rats.


  • Veterans Affairs Support