The complement factor 5a receptor 1 has a pathogenic role in chronic inflammation and renal fibrosis in a murine model of chronic pyelonephritis.

Abstract:

:Complement factor 5a (C5a) interaction with its receptor (C5aR1) contributes to the pathogenesis of inflammatory diseases, including acute kidney injury. However, its role in chronic inflammation, particularly in pathogen-associated disorders, is largely unknown. Here we tested whether the development of chronic inflammation and renal fibrosis is dependent on C5aR1 in a murine model of chronic pyelonephritis. C5aR1-deficient (C5aR1-/-) mice showed a significant reduction in bacterial load, tubule injury and tubulointerstitial fibrosis in the kidneys following infection, compared with C5aR1-sufficient mice. This was associated with reduced renal leukocyte infiltration specifically for the population of Ly6Chi proinflammatory monocytes/macrophages and reduced intrarenal gene expression of key proinflammatory and profibrogenic factors in C5aR1-/- mice following infection. Antagonizing C5aR1 decreased renal bacterial load, tissue inflammation and tubulointerstitial fibrosis. Ex vivo and in vitro studies showed that under infection conditions, C5a/C5aR1 interaction upregulated the production of proinflammatory and profibrogenic factors by renal tubular epithelial cells and monocytes/macrophages, whereas the phagocytic function of monocytes/macrophages was down-regulated. Thus, C5aR1-dependent bacterial colonization of the tubular epithelium, C5a/C5aR1-mediated upregulation of local inflammatory responses to uropathogenic E. coli and impairment of phagocytic function of phagocytes contribute to persistent bacterial colonization of the kidney, chronic renal inflammation and subsequent tubulointerstitial fibrosis.

journal_name

Kidney Int

journal_title

Kidney international

authors

Choudhry N,Li K,Zhang T,Wu KY,Song Y,Farrar CA,Wang N,Liu CF,Peng Q,Wu W,Sacks SH,Zhou W

doi

10.1016/j.kint.2016.04.023

subject

Has Abstract

pub_date

2016-09-01 00:00:00

pages

540-54

issue

3

eissn

0085-2538

issn

1523-1755

pii

S0085-2538(16)30197-1

journal_volume

90

pub_type

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