Abstract: TH-PO279

C5aR1 Promotes the Pathogenesis of Acute Pyelonephritis

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Li, Ke, Xi'an Jiaotong University, Xi'an, China
  • Sacks, Steven H., King's College London, London, United Kingdom
  • Zhou, Wuding, King's College London, London, United Kingdom
Background

Our recent work in a murine mode of chronic pyelonephritis has shown that C5a/C5aR1 interaction play an important role in the pathogenesis of chronic renal inflammation and tubulointerstitial fibrosis. However, the role of C5aR1 in acute pyelonephritis is presently unknown.

Methods

To investigate this, we employed a murine mode of acute pyelonephritis, induced by human UPEC strain J96, in combination with either C5aR1 deficiency (C5aR1-/- mice), or chemical blockade of C5a/C5aR1 interactions, to determine the roles of C5aR1 in acute renal infection. In addition, we performed a serious of ex vivo (renal tissue) and in vitro (primary cultures of renal tubular epithelial cells [RTEC]) experiments to examine the relationship between C5a/C5aR1 and mannosyl residue expression and UPEC adhesion/colonisation in RTEC. We also explored the signal transduction mechanisms by which C5a regulates mannosyl residue expression in RTEC. Bone marrow chimera experiments were performed to specifically evaluate the relative contributions of C5aR1 expressed on renal and myeloid cells.

Results

In vivo analysis showed that C5aR1 deficient mice or C5aR1 antagonist treated mice displayed reduced bacterial load and tissue destruction in the kidney, which is associated with reduced expression of mannosyl residues (a ligand for type 1 fimbriae of E coli) at luminal surface of renal tubules and early bacterial colonization of the tubular epithelium. Chimera experiments suggest that C5aR1 on renal cells plays a more prominent role in this model. In vitro analysis of renal tubular epithelial cells showed that mannosyl-dependent adhesion and invasion were enhanced by C5a-mediated ERK1/2 and NF-kB phosphorylation and TNF-α production.

Conclusion

Our data demonstrate a pathogenic role for C5a/C5aR1 in acute pyelonephritis and define novel mechanism by which C5aR1 signalling enhances mannosyl residue-dependent colonisation of renal tubular epithelium that increases susceptibility to a common and harmful urinary pathogen, opening up a new avenue for therapeutic targeting.

Funding

  • Government Support - Non-U.S.