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Abstract: FR-PO078

Metabolic Alterations Following Renal Ischemia Reperfusion in Rats

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Bracken, Christina, Mitobridge, an Astellas company, Cambridge, Massachusetts, United States
  • Stanwix, Jeff H., Mitobridge, an Astellas company, Cambridge, Massachusetts, United States
  • Pulito, Katelyn, Mitobridge, an Astellas company, Cambridge, Massachusetts, United States
  • Krishna, Mahati, Syngene International Pvt. Ltd., Bangalore, India
  • Tozzo, Effie, Mitobridge, an Astellas company, Cambridge, Massachusetts, United States

Acute kidney injury (AKI) is a major health issue, associated with high morbidity, mortality, fibrosis and CKD. Ischemia reperfusion injury (IRI) during surgical procedures such as coronary artery bypass grafting or transplantation can cause AKI. In this study, we sought to characterize the timecourse of molecular and cellular pathophysiological consequences of IRI in the rat.


Sprague-Dawley rats underwent 45-minute bilateral ischemia followed by reperfusion for 1, 4, 8, 12, 24, 48, 72 hours (hr) or 14 days. We characterized renal injury by measuring plasma and urine biomarkers at all timepoints. We also evaluated tubular injury/repair and subsequent development of renal fibrosis. To delineate IR-induced metabolic changes, we examined gene expression of metabolic pathways including pyruvate handling, fatty acid oxidation, oxidative stress, and mitochondrial homeostasis. We also evaluated NAD+ utilization and biosynthesis using mass spectrometry and ELISA based methods.


IR-AKI resulted in varying kinetics of plasma and urinary biomarkers. Plasma creatinine and NGAL were elevated 4hr post AKI, and peaked at 24hr, whereas BUN increase was slightly delayed. Urinary NGAL and KIM-1 had similar time-dependent profiles peaking at 24-48hr, whereas urinary FABP-1 excretion peaked at 4hr, then rapidly declined. Tubular and vascular injury were evident 4hr post AKI with proliferation occurring from 24 - 72hr. Gene expression analysis revealed downregulation of proximal tubular cell-specific genes, which suggests loss or de-differentiation. By day 14 post injury, there was clear biochemical and histological evidence for fibrosis despite normal GFR. Renal IRI negatively affected the expression of genes regulating oxidative stress, mitochondrial function, pyruvate handling and fatty acid metabolism through the reperfusion phase. Furthermore, data revealed reduced gene expression of NAD+ biosynthetic enzymes concomitant with a drop of NAD+, increased NAD+ utilization and breakdown products.


Together, our data reveal dysregulation of metabolic processes that contribute to the pathophysiology of IR-induced AKI and may allow for investigation of previously unexplored therapeutic avenues.


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