Complement Factor B Production in Renal Tubular Cells and Its Role in Sodium Transporter Expression During Polymicrobial Sepsis

• Published in: Critical care medicine Vol. 44; no. 5; p. e289
• Main Authors: Li, Dan, Zou, Lin, Feng, Yan, Xu, Ganqiong, Gong, Yu, Zhao, Gaofeng, Ouyang, Wen, Thurman, Joshua M, Chao, Wei
• Format: Journal Article
• Language: English
• Published: United States 01.05.2016
• Subjects: Animals; Biological Transport, Active - physiology; Complement Factor B - biosynthesis; Disease Models, Animal; Down-Regulation; Epithelial Sodium Channels - genetics; Female; Gene Expression; Humans; Kidney - physiopathology; Kidney Tubules, Proximal - metabolism; Male; Mice; Mice, Inbred C57BL; NF-kappa B - antagonists & inhibitors; Nitriles - pharmacology; Potassium Channels - genetics; Reverse Transcriptase Polymerase Chain Reaction; Sepsis - physiopathology; Signal Transduction - physiology; Sulfones - pharmacology; Toll-Like Receptors - agonists; Toll-Like Receptors - genetics; Up-Regulation
• DOI: 10.1097/CCM.0000000000001566

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. Animal study. Laboratory investigation. C57BL/6 J wild-type, complement factor B(-/-), and Nfkb1(tm1Bal) p50(-/-) mice. 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-κB 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. 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-κB signaling, and in mouse tubular epithelial cells deficient in p50 subunit of nuclear factor-κB. 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-α1 following sepsis. 1) Toll-like receptor 3/4 activation is sufficient to induce complement factor B production via nuclear factor-κB 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.