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Reduction of activated macrophages after ischaemiareperfusion injury diminishes oxidative stress and ameliorates renal damage

: Fet, N.G.; Fiebeler, A.; Klinge, U.; Park, J.K.; Barth, S.; Thepen, T.; Tolba, R.H.


Nephrology, dialysis, transplantation : NDT 27 (2012), Nr.8, S.3149-3155
ISSN: 0931-0509
ISSN: 1460-2385
Fraunhofer IME ()

Macrophages are major effectors of the local inflammatory response syndrome (LIRS) and influence the extent of ischaemia/reperfusion injury, thereby impacting organ function. Several subgroups of macrophages exist, representing distinct modes of action. The specific role of the subset expressing Fc gamma receptor (FcR) 1 in the activated state of macrophages is poorly defined. We induced a LIRS via 30 min of ischaemia in uninephrectomized rats, transgenic for the human FcR1. Six hours after reperfusion, the treatment group was injected with a recombinant immunotoxin (IT) H22(scFv)-ETA targeted against human FcR1, which induced apoptosis of target cells. The placebo group received normal saline (NS). Contralateral kidneys served as healthy controls (Ctr). After 24 h of reperfusion, the animals were analysed. Targeted treatment with IT resulted in preserved renal function [NS versus IT treatment and baseline (creatinine: 69.2 2.6, 54.7 3.4 and 27.3 1.0 mol/L; P 0.001)]. The number of all infiltrating monocytes were significantly reduced (CD68-positive cells per view field: NS 3.8 0.4, IT 2.5 0.2 and Ctr 1.2 0.4; P 0.05), renal histology improved and there was a reduced expression of renal fibronectin (NS 4.0 0.4, IT 2.3 0.2 and Ctr 1.1 0.1; P 0.001). Following IT administration, we also observed less expression of renal monocyte chemoattractant protein-1-positive cells per view field (NS 19.0 1, IT 10.1 0.8 and Ctr 2.0 0.3; P 0.001) as well as reduced systemic and local oxidative stress [serum malondialdehyde (MDA): NS 340 30, IT 224 36 versus baseline 140 5 nmol/mL; P 0.01]; renal MDA arbitrary units of fluorescence intensity: NS 3.7 0.2, IT 1.8 0.3 and Ctr 0.4 0.2; P 0.001. Reduction of FcR1-up-regulated monocytic cells leads to preserved renal function and morphology in a rat model of ischaemia-triggered LIRS. Our results show that targeting activated macrophages is a valuable approach for ameliorating ischaemia-induced tissue injury.