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Abstract: SA-PO602

Hypoxic Preconditioning Suppresses Renal Inflammation in Ischemic and Septic AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Torosyan, Rafael, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Rajendran, Ganeshkumar, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Schonfeld, Michael P., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Kapitsinou, Pinelopi P., University of Kansas Medical Center, Kansas City, Kansas, United States
Background

Prolyl-hydroxylases (PHDs) have emerged as safeguards of cellular metabolism through their oxygen sensing function, which enables them to regulate the activity of hypoxia-inducible factors (HIF). We previously reported that activation of HIF signaling via pharmacologic inhibition of PHDs (PHI) protects against kidney ischemia reperfusion injury (IRI). Here, we investigated whether HIF activation through exposure to normobaric hypoxia mimics the renoprotection induced by PHI. Using an unbiased metabolomic approach, we identified conserved metabolic responses between these interventions.

Methods

C57BL/6 male mice aged 8-10 weeks were subjected to normobaric hypoxia (8% O2) for 48 hours prior to induction of AKI via unilateral renal artery clamping (IRI) or LPS administration. Untargeted metabolomic screening by a GC/MS and LC/MS based platform was performed in sera from mice treated with PHI or exposed to acute hypoxia.

Results

Pre-ischemic exposure to normobaric hypoxia attenuated kidney injury at day 3 post IRI as indicated by improved kidney histogical scores and a 2.3-fold reduction of Kim1 mRNA levels in kidney homogenates compared to normoxic controls (n=7-8, P=0.0002). Furthermore, hypoxic preconditioning suppressed the expression of pro-inflammatory genes Vcam1 and Tnfα by 2.6-fold (n=7-8, P<0.0001) and diminished the infiltration of Ly6B.2+ve cells in injured kidneys by 85% (P<0.0001) compared to controls. In a septic model of AKI induced by LPS, hypoxic preconditioning suppressed the transcripts of Tnfα and Il-6 by 2.3- and 5-fold respectively (Day 1 post LPS, n= 11-14; p < 0.009). Comparative untargeted metabolomic analysis revealed that exposure to hypoxia and pharmacologic PHD inhibition led to significantly overlapping alterations in serum metabolome. For instance, serum levels of α-ketoglutarate, a TCA cycle metabolite, were reduced by 60% in the setting of hypoxic preconditioning (n=8, P <0.0001) and by 36% with PHD inhibition (n=8, P = 0.004) compared to their corresponding controls.

Conclusion

Our data demonstrate that exposure to normobaric hypoxia attenuates kidney inflammation in both IRI-and sepsis-induced AKI. Furthermore, PHD inhibition induced by exposure to hypoxia or pharmacologic means lead to metabolic reprogramming, which may play a critical role in regulating inflammatory responses in the context of AKI.

Funding

  • NIDDK Support