Complement Factor B Production in Renal Tubular Cells and Its Role in Sodium
Transporter Expression During Polymicrobial Sepsis
#MMPMID26757165
Li D
; Zou L
; Feng Y
; Xu G
; Gong Y
; Zhao G
; Ouyang W
; Thurman JM
; Chao W
Crit Care Med
2016[May]; 44
(5
): e289-99
PMID26757165
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OBJECTIVES: Toll-like receptors and complement are two components of the innate
immunity. Complement factor B is essential for the alternative pathway of
complement activation. We have recently reported that complement factor B is
significantly up-regulated in the kidney and may contribute to acute tubular
injury in an animal model of sepsis. This study investigates the mechanisms
responsible for the complement factor B up-regulation and its role in sodium
transporter expression in tubular cells during sepsis. DESIGN: Animal study.
SETTING: Laboratory investigation. SUBJECTS: C57BL/6 J wild-type, complement
factor B(-/-), and Nfkb1(tm1Bal) p50(-/-) mice. INTERVENTIONS: Human proximal
tubular cells and mouse tubular epithelial cells were stimulated with Toll-like
receptor agonists. Bay 11-7082 was used to block nuclear factor-?B pathway.
Alternative pathway activation was detected by C3 zymosan deposition.
Polymicrobial sepsis was created by cecal ligation and puncture. Sodium
transporter gene expression was determined by quantitative reverse
transcriptase-polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: The
agonists for Toll-like receptor 4 (lipopolysaccharide) or Toll-like receptor 3
(polyinosinic-polycytidylic acid) induced a marked increase in complement factor
B expression in human proximal tubular cells and mouse tubular epithelial cells
both at gene and protein levels. The Toll-like receptor 1/2 agonist, Pam3cys,
induced complement factor B production only in human proximal tubular cells, not
in mouse tubular epithelial cells. The Toll-like receptor 9 ligand, CpG
oligodeoxynucleotides failed to induce complement factor B production either in
human proximal tubular cells or in mouse tubular epithelial cells.
Lipopolysaccharide/polyinosinic-polycytidylic acid-induced complement factor B
up-regulation was blocked by Bay 11-7082, a potent inhibitor of nuclear factor-?B
signaling, and in mouse tubular epithelial cells deficient in p50 subunit of
nuclear factor-?B. Media from the lipopolysaccharide-treated mouse tubular
epithelial cell cultures contained de novo synthesized complement factor B and
led to functional alternative pathway activation. In a cecal ligation and
puncture model, wild-type septic mice had down-regulated expression of sodium
transporters in the kidney compared with the sham. In comparison, complement
factor B mice or mice treated with anti-complement factor B displayed preserved
levels of Na?/K? ATPase-?1 following sepsis. CONCLUSIONS: 1) Toll-like receptor
3/4 activation is sufficient to induce complement factor B production via nuclear
factor-?B pathway and to enhance alternative pathway activation in the kidney
tubular epithelial cells. 2) Complement factor B may contribute to the
down-regulation of certain sodium transporter expression during sepsis.
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