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Abstract :
[en] Ischemic preconditioning(IPC) attenuate the severity of renal ischemia/reperfusion(I/R). Irradiation induces renal IPC in mice, although the pathways remain largely unknown. Here, we investigate the circuits involved in renal irradiation, assess the functional impact of renal irradiation applied I/R injury, and test whether Sunitinib-mediated inhibition of the angiogenesis prevents irradiation-associated IPC.
Methods: Exp1: Renal irradiation(8Gy) was performed in C57bl/6 mice(n=10). 1month later, total kidney RNA was extracted from irradiated and control mice for 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 signaling pathways. Expressions of vascular markers (CD31, VEGF) showed an increase at both mRNA and protein levels in irradiated kidneys(p<0.01). Exp2: Following I/R, BUN and SCr levels were lower in irradiated mice(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). 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. Exp3: One-way ANOVA 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 activate angiogenesis, leads to IPC, with preserved renal function post I/R. Exposure to the anti-angiogenic drug Sunitinib post-irradiation prevents the irradiation-induced IPC.
