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Abstract: PO0426

The Irradiation-Induced Renal Ischemic Preconditioning Is Blunted by the Oral Administration of the Anti-Angiogenic Agent Sunitinib

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Khbouz, Badr, Universite de Liege Faculte de Medecine, Liege, Liège, Belgium
  • Rowart, Pascal, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
  • Lallemand, François, Universite de Liege Faculte de Medecine, Liege, Liège, Belgium
  • Laurence, Poma, Universite de Liege Faculte de Medecine, Liege, Liège, Belgium
  • Krzesinski, Jean-Marie H., Universite de Liege Faculte de Medecine, Liege, Liège, Belgium
  • Jouret, Francois, Universite de Liege Faculte de Medecine, Liege, Liège, Belgium

Group or Team Name

  • Laboratory of Translational Research in Nephrology (LTRN) - GIGA Institute
Background

Whole-body irradiation has been suggested to induce renal ischemic preconditioning(RIP) in mice, possibly via angiogenesis. First, we comprehensively investigate the pathways involved in renal irradiation. Next, we assess the functional impact of renal irradiation applied before renal ischemia/reperfusion(I/R) injury. Finally, we test whether Sunitinib-mediated inhibition of the angiogenesis prevents irradiation-associated RIP.

Methods

Exp1: Renal irradiation(8.56 Gy) was performed in male C57bl/6 mice(n=10). One month later, total kidney RNA was extracted from irradiated and control(n=5) mice for comparative RNA-Seq. Exp2: After renal irradiation, the right kidneys were removed, and the left kidneys undergo ischemia(30min)/reperfusion(48h) at Days 7-14-28 post irradiation(n=8). Exp3: Following the same protocol of I/R at Day14, 3 groups were compared(n=8): 1/irradiation; 2/irradiation and gavage with Sunitinib from Day2 to 13; 3/control group without irradiation or gavage.

Results

Exp1: RNAseq showen up-regulation of angiogenesis signalling pathways. Expressions of angiogenesis markers(CD31, VEGF) showed an increase at both mRNA and protein levels in irradiated kidneys(p<0.01). Exp2: Following I/R, Blood Urea Nitrogen(BUN) and Creatinine(SCr) levels were lower in the irradiated mice compared to controls: (BUN: 86.2±6.8 vs. 454.5±27.2mg/dl; SCr: 0.1±0.01 vs. 1.7±0.2mg/dl, p<0.01). The renal infiltration by CD11b-(187±32 vs 477±20/mm2) and F4-80-positive cells(110±22 vs 212±25/mm2) was reduced in the irradiated group. VEGF and CD31 expression was increased in irradiated kidneys at both mRNA and protein levels(p<0,01). Exp3: One-way analysis of variance followed by Tukey’s test showed that, following I/R, BUN and SCr levels were lower in the irradiated group compared to controls(BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), and in irradiated group compared to the irradiated-exposed group to Sunitinib(BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl; p<0.01).

Conclusion

Renal irradiation induces the activation of angiogenesis in mice. Renal irradiation leads to RIP, with preserved renal function and attenuated inflammation post I/R. Exposure to the anti-angiogenic drug Sunitinib post-irradiation prevents the irradiation-induced RIP.

Funding

  • Government Support – Non-U.S.