Although complement activation and deposition have been associated with a variety of glomerulopathies, the pathogenic mechanisms by which complement directly mediates renal injury remain to be fully elucidated. Renal parenchymal tissues express a limited repertoire of receptors that directly bind activated complement proteins. We report the renal expression of the receptor for the C3 cleavage product C3a, a member of the anaphylatoxin family. C3aR is highly expressed in normal human and murine kidney, as demonstrated by immunohistochemistry and in situ hybridization. Its distribution is limited to epithelial cells only, as glomerular endothelial and mesangial cells showed no evidence of C3aR expression. The C3aR is also expressed by primary renal proximal tubular epithelial cells in vitro as demonstrated by FACS, Western blot, and RT-PCR. In vitro C3aR is functional in terms of its capacity to bind 125I-labeled C3a and generate inositol triphosphate. Finally, using microarray analysis, four novel genes were identified and confirmed as transcriptionally regulated by C3aR activation in proximal tubular cells. These studies define a new pathway by which complement activation may directly modulate the renal response to immunologic injury.
Animal models provide vital tools to explicate the pathogenesis of atherosclerosis. Accordingly, we established two atherosclerosis-prone mice models: (i) mice lacking the LDL (low-density lipoprotein) receptor (LDLR) and the ability to edit apo (apolipoprotein) B mRNA (Apobec1; designated LDb : LDLR-/- Apobec1-/-), and (ii) mice with the LDb background, who also overexpressed human apoB100 (designated LTp : LDLR-/- Apobec1-/- ERhB+/+). Both LDb and LTp mice had markedly elevated levels of LDL and increased levels of NEFAs (non-esterified fatty acids) compared with C57BL/6 wild-type mice. However, fasting glucose and insulin levels in both animals were not different than those in C57BL/6 wild-type mice. It has been suggested that PAF-AH (platelet-activating factor acetylhydrolase) increases susceptibility to vascular disease. Both LDb and LTp mice had significantly higher PAF-AH mRNA levels compared with C57BL/6 wild-type mice. PAF-AH gene expression was also significantly influenced by age and sex. Interestingly, PAF-AH mRNA levels were significantly higher in both LTp male and female mice than in the LDb mice. This increased PAF-AH gene expression was associated with elevated plasma PAF-AH enzyme activities ( LTp > LDb > C57BL/6 ). Moreover, a greater proportion of PAF-AH activity was associated with the apoB-containing lipoproteins: 29% in LTp and 13% in LDb mice compared with C57BL/6 wild-type animals (6.7%). This may explain why LTp mice developed more atherosclerotic lesions than LDb mice by 8 months of age. In summary, increased plasma NEFAs, PAF-AH mRNA and enzyme activities are associated with accelerated atherogenesis in these animal models.
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