[en] INTRODUCTION | Renal ischemia/reperfusion (I/R) is the leading cause of acute kidney
injury (AKI). Ischemic preconditioning (IPC) may help to attenuate the severity of I/Rassociated AKI. Whole-body irradiation induces renal IPC in mice, although the pathways
remain largely unknown. Furthermore, the impact of kidney-centred irradiation on renal
resistance against I/R has not been studied. First, we comprehensively investigate the
pathways involved in renal irradiation. Next, we assess the functional impact of renal
irradiation applied I/R injury. Finally, we test whether Sunitinib-mediated inhibition of the
angiogenesis prevents irradiation-associated IPC.
METHODS | Exp1: Renal irradiation (8.5Gy) 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 IPC, with preserved renal function and attenuated inflammation post
I/R. Exposure to the anti-angiogenic drug Sunitinib post-irradiation prevents the
irradiation-induced IPC.
Research center :
GIGA‐R - Giga‐Research - ULiège
Disciplines :
Urology & nephrology
Author, co-author :
Khbouz, Badr ; Université de Liège - ULiège > Département des sciences cliniques > Néphrologie
LALLEMAND, François ; Centre Hospitalier Universitaire de Liège - CHU > Département de Physique Médicale > Service médical de radiothérapie