Abstract: TH-PO339

PPARδ Modulator MTB-2 Enhances FAO In Vitro and Attenuates Ischemia-Reperfusion-Induced Gene Expression Changes In Vivo 48 Hours and 14 Days Post AKI

Session Information

Category: Acute Kidney Injury

  • 002 AKI: Repair and Regeneration


  • Bracken, Christina, Mitobridge, Cambridge, Massachusetts, United States
  • Stanwix, Jeff H, Mitobridge, Cambridge, Massachusetts, United States
  • Hoang, Hien G, Mitobridge, Cambridge, Massachusetts, United States
  • Bell, Eric, Mitobridge, Cambridge, Massachusetts, United States
  • Tozzo, Effie, Mitobridge, Cambridge, Massachusetts, United States

Ischemic acute kidney injury (AKI) is characterized by persistent proximal tubule mitochondrial dysfunction. Due to their highly oxidative metabolism, proximal tubule cells (PTC) 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, offering a potential therapeutic treatment for AKI.


Human hTERT RPTECs were treated with MTB-2 and analyzed for PPARδ target gene expression and their ability to utilize palmitate. Sprague-Dawley 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. At 48 hours and 14 days post reperfusion kidney cortex gene expression was assessed by qPCR.


MTB-2 significantly increased expression of PPARδ-target genes associated with mitochondrial FAO (such as Cpt1a) and resulted in enhanced palmitate oxidation in hTERT RPTECs. In vivo, MTB-2 reduced plasma and urinary biomarkers of AKI at 24 and 48 hours. To elucidate the mechanism by which MTB-2 modulation of PPARδ improved AKI we measured expression of proximal tubulec abundance, mitochondrial homeostasis, kidney injury and fibrosis genes at 48 hours and 14 days post AKI. At 48 hours MTB-2 resulted in partial restoration of proximal tubules denoted by increased expression of PTC genes; this effect was maintained through 14 days post AKI. At the same time points, PPARδ modulation mitigated IR-induced reduction of genes regulating mitochondrial transcription such as PGC1α and many nuclear and mitochondrial-encoded transcripts of electron transport chain proteins. At both 48 hours and 14 days post AKI MTB-2 decreased the expression of kidney injury genes KIM-1and NGAL. Genes associated with fibrosis, such as, Col1a1, were induced at 14 days post AKI and MTB-2 treatment attenuated their upregulation.


Selective PPARδ modulation by MTB-2 after AKI in rats recovered renal function through preservation of proximal tubular and mitochondrial gene expression and reduction of kidney injury and profibrotic genes.