C5aR1 promotes acute pyelonephritis induced by uropathogenic E. coli
Ke Li, Kun-Yi Wu, Weiju Wu, Na Wang, Ting Zhang, Naheed Choudhry, Yun Song, Conrad A. Farrar, Liang Ma, Lin-lin Wei, Zhao-Yang Duan, Xia Dong, En-Qi Liu, Zong-Fang Li, Steven H. Sacks, Wuding Zhou
Ke Li, Kun-Yi Wu, Weiju Wu, Na Wang, Ting Zhang, Naheed Choudhry, Yun Song, Conrad A. Farrar, Liang Ma, Lin-lin Wei, Zhao-Yang Duan, Xia Dong, En-Qi Liu, Zong-Fang Li, Steven H. Sacks, Wuding Zhou
View: Text | PDF
Research Article Nephrology

C5aR1 promotes acute pyelonephritis induced by uropathogenic E. coli

Abstract

C5a receptor 1 (C5aR1) is a G protein–coupled receptor for C5a and also an N-linked glycosylated protein. In addition to myeloid cells, C5aR1 is expressed on epithelial cells. In this study, we examined the role of C5aR1 in bacterial adhesion/colonization of renal tubular epithelium and addressed the underlying mechanisms of this role. We show that acute kidney infection was significantly reduced in mice with genetic deletion or through pharmacologic inhibition of C5aR1 following bladder inoculation with uropathogenic E. coli (UPEC). This was associated with reduced expression of terminal α-mannosyl residues (Man; a ligand for type 1 fimbriae of E. coli) on the luminal surface of renal tubular epithelium and reduction of early UPEC colonization in these mice. Confocal microscopy demonstrated that UPEC bind to Man on the luminal surface of renal tubular epithelium. In vitro analyses showed that C5a stimulation enhances Man expression in renal tubular epithelial cells and subsequent bacterial adhesion, which, at least in part, is dependent on TNF-α driven by C5aR1-mediated intracellular signaling. Our findings demonstrate a previously unknown pathogenic role for C5aR1 in acute pyelonephritis, proposing a potentially novel mechanism by which C5a/C5aR1 signaling mediates upregulation of carbohydrate ligands on renal tubules to facilitate UPEC adhesion.

Authors

Ke Li, Kun-Yi Wu, Weiju Wu, Na Wang, Ting Zhang, Naheed Choudhry, Yun Song, Conrad A. Farrar, Liang Ma, Lin-lin Wei, Zhao-Yang Duan, Xia Dong, En-Qi Liu, Zong-Fang Li, Steven H. Sacks, Wuding Zhou

×

Figure 2

C5aR1 deficiency protects mice from acute pyelonephritis.

Options: View larger image (or click on image) Download as PowerPoint
C5aR1 deficiency protects mice from acute pyelonephritis. (A) Bacterial ...
(A) Bacterial loads in kidney tissues of WT and C5aR1–/– mice at 24, 48, and 72 hours postinfection (hpi) determined by bacterial plate count assay (n = 10/group). (B) Representative images of PAS staining of kidney sections of WT and C5aR1–/– mice at 72 hpi. Top panel: Cross-sections of the whole kidney. Scale bars: 1,000 μm. Middle and lower panels: Higher magnification images corresponding to the boxed regions in the above panel. Scale bars: 250 μm. (C) Histological scores of kidney sections of WT and C5aR1–/– mice at 72 hpi (n = 8/group). (D) Relative mRNA levels of proinflammatory mediators in infected kidney tissues of WT and C5aR1–/– mice at 6 hpi determined by RT-qPCR (n = 8/group). The dotted line across each graph represents the gene expression level of normal kidney tissue, which is similar between WT and C5aR1–/– mice. (E) Quantification of inflammatory cells in infected kidney tissues of WT and C5aR1–/– mice at 24 hpi. The dotted line across each graph represents the levels of inflammatory cells in normal kidney tissue, which is similar between WT and C5aR1–/– mice. MO/MΦ, monocytes/macrophages. For all data, each data point represents an individual mouse. Mann-Whitney test was used for CFU data in A. Unpaired 2-tailed Student’s t test was used for the data in B–E. *P < 0.05, **P < 0.005, ***P < 0.001.