title: C-reactive protein exacerbates renal ischemia-reperfusion injury.
abstract: Renal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), occurring with hypotension and cardiovascular surgery and inevitably during kidney transplantation. 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) and human CRP transgenic mice (CRPtg) to bilateral renal IRI (both pedicles clamped for 30 min at 37°C then reperfused for 24 h). Serum human CRP level was increased approximately sixfold after IRI in CRPtg (10.62 ± 1.31 μg/ml at baseline vs. 72.01 ± 9.41 μg/ml at 24 h) but was not elevated by sham surgery wherein kidneys were manipulated but not clamped. Compared with WT, serum creatinine, urine albumin, and histological evidence of kidney damage were increased after IRI in CRPtg mice. RT-PCR analysis of mRNA isolated from whole kidneys of CRPtg and WT subjected to IRI revealed that in CRPtg kidneys 1) upregulation of markers of macrophage classical activation (M1 markers) was blunted, 2) downregulation of markers of macrophage alternative activation (M2 markers) was more robust, and 3) expression of the activating receptor FcγRI was increased. Our finding that CRP exacerbates IRI-induced AKI, perhaps by shifting the balance of macrophage activation and FcγR expression towards a detrimental portfolio, might make CRP a promising therapeutic target for the treatment of AKI.
authors.affiliation: Department of Medicine, University of Alabama, Birmingham, AL, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Pegues
authors.forename: Mark A
authors.initials: MA
authors.lastname: McCrory
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Zarjou
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Szalai
mesh_terms: D000419:Albuminuria; D000818:Animals; D002097:C-Reactive Protein / Q000235:genetics / Q000502:physiology*; D003404:Creatinine / Q000097:blood; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000097:blood; D007668:Kidney / Q000098:blood supply* / Q000473:pathology; D007674:Kidney Diseases / Q000097:blood / Q000209:etiology; D008262:Macrophage Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017452:Receptors, IgG / Q000235:genetics; D015427:Reperfusion Injury / Q000150:complications / Q000503:physiopathology*
chemical_list: D017452:Receptors, IgG; D002097:C-Reactive Protein; D003404:Creatinine
keywords: AKI; acute phase proteins; alternatively activated macrophages
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