Renal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) after kidney transplantation, hypotension, and cardiovascular surgery. Mortality from AKI is high due to incomplete knowledge of the pathogenesis of IRI and the lack of an effective therapy. Inflammation accompanies IRI and increases the blood level of C-reactive protein (CRP), a biomarker of worsened outcomes in AKI. To test if CRP is causal in AKI we subjected wild type mice (WT), human CRP transgenic mice (CRPtg) and CRP deficient mice (CRP-/-) to bilateral renal IRI (both pedicles clamped for 30 min at 37°C then reperfused for 24 h). Serum human CRP level was increased ~six-fold after IRI in CRPtg (11.58 ± 1.40 µg/ml at baseline versus 65.75 ± 7.90 µg/ml at 24 h) but was not elevated by sham surgery wherein kidneys were manipulated but not clamped. Compared to WT, serum creatinine and urine albumin was increased after IRI in CRPtg mice. Histological evidence of kidney damage was greater in CRPtg than in WT, whereas CRP-/- kidneys were protected. RT-PCR analysis of mRNA isolated from whole kidneys subjected to IRI revealed that expression of FcγRs increased in CRP-/- kidneys and markers of macrophage activation indicated a stronger classically activated (M1) macrophage response in CRPtg kidneys. Our finding that CRP exacerbates IRI induced AKI by shifting the balance of beneficial and detrimental FcγRs and macrophages, makes CRP a promising therapeutic target for the treatment of AKI.
- Copyright © 2013 by The American Association of Immunologists, Inc.