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Abstract: SA-PO561

Inhibition of PARP1 Attenuates Rat Renal Ischemia Reperfusion Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Bracken, Christina, Mitobridge, an Astellas company, Cambridge, Massachusetts, United States
  • Pulito, Katelyn, Mitobridge, an Astellas company, Cambridge, Massachusetts, United States
  • Stanwix, Jeff H., Mitobridge, an Astellas company, Cambridge, Massachusetts, United States
  • Shine, Robert W., Mitobridge, an Astellas company, Cambridge, Massachusetts, United States
  • Krishna, Mahati, Syngene International Pvt. Ltd., Bangalore, India
  • Ji, Nan, Mitobridge, an Astellas company, Cambridge, Massachusetts, United States
  • Tozzo, Effie, Mitobridge, an Astellas company, Cambridge, Massachusetts, United States
  • Stickens, Dominique, Mitobridge, an Astellas company, Cambridge, Massachusetts, United States
Background

Renal ischemia reperfusion injury (IRI) generates superoxide and other reactive species and induces PARP1 activation to repair ROS-mediated DNA strand breaks. However, PARP1 activation depletes NAD+ and ATP, and promotes pro-inflammatory signal transduction, all of which can exacerbate IRI. We hypothesized that inhibiting PARP1 would decrease/prevent NAD+ depletion and reduce IR-induced acute kidney injury (AKI).

Methods

We evaluated the ability of a novel and selective PARP1 inhibitor, Cmpd A to boost NAD+ and mitochondrial respiration in control and cisplatin challenged human proximal tubule cells (PTC). Sprague-Dawley rats underwent a 50 minute bilateral IR and were administered Cmpd A (or vehicle), twice daily at 0.1, 0.3, 1, 5, or 15 mg/kg by intravenous injection for 2 days, beginning at 4 hours post reperfusion. Cmpd A activity was assessed by measuring renal PAR levels, NAD+ and its breakdown products, by ELISA or mass spectrometry. Renal injury biomarkers were measured in plasma at 24 and 48 hr post reperfusion and tubular injury was evaluated by histopathology. Gene expression analysis for inflammatory mediators and Vegfa were assessed using Nanostring technology.

Results

Cmpd A treatment increases NAD+ levels by 35% and enhances mitochondrial respiration under normal PTC culture conditions while preventing nephrotoxin-induced NAD+ depletion when PTC are treated with cisplatin. In the rat model of IR-AKI, Cmpd A lowers plasma creatinine and BUN dose dependently at 24 and 48 hr post injury. This translates to improved renal function via increased creatinine clearance and normalization of fractional excretion of Na+ (FENa). Assessment of kidney histopathology at 48 hr post reperfusion revealed that Cmpd A normalizes renal tubular architecture. In addition, Cmpd A treatment reduces IR-induced upregulation of inflammatory mediators and restores the downregulation of Vegfa gene expression.

Conclusion

Dosing of a selective PARP1 inhibitor after an ischemic AKI event in rats recovers renal and tubular function. Mechanistically, our data suggest that this effect is mediated by a reduction of pro-inflammatory signaling, preservation of Vegfa and increase of NAD+ levels.

Funding

  • Commercial Support