RESUMO
B cell-targeted therapies are effective for treating multiple different kidney diseases in humans and also protect mice from Adriamycin nephropathy. Because glomerular IgM is frequently seen in both humans and mice with "nonimmune" forms of glomerular disease, we hypothesized that natural IgM binds to epitopes displayed in the injured glomerulus, exacerbating injury. To test this hypothesis, we induced Adriamycin nephropathy in BALB/C mice that cannot secrete soluble IgM (sIgM-/- mice) and compared them with BALB/C controls. Contrary to our prediction, we found that female sIgM-/- mice developed higher mortality and more severe kidney injury after injection of Adriamycin. The absence of soluble IgM did not reduce glomerular complement activation, and IgG was seen deposited within the injured glomeruli. Furthermore, we discovered that female sIgM-/- mice have higher levels of anti-cardiolipin IgG, and that IgG from these mice binds to epitopes in the injured kidney. These findings indicate that natural IgM may prevent generation of autoreactive IgG. Circulating levels of anti-cardiolipin IgG decreased after induction of kidney injury in female mice, consistent with deposition of the Abs in injured tissues. Better understanding of the mechanisms by which the immune system modulates and amplifies kidney injury may enable the development of targeted therapies to slow kidney disease progression.
Assuntos
Imunoglobulina M , Nefropatias , Animais , Feminino , Camundongos , Doxorrubicina , Epitopos , Imunoglobulina G , Camundongos Endogâmicos BALB CRESUMO
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-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. 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-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 Naâº/K⺠ATPase-α1 following sepsis. CONCLUSIONS: 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.
Assuntos
Fator B do Complemento/biossíntese , Rim/fisiopatologia , Sepse/fisiopatologia , Animais , Transporte Biológico Ativo/fisiologia , Modelos Animais de Doenças , Regulação para Baixo , Canais Epiteliais de Sódio/genética , Feminino , Expressão Gênica , Humanos , Túbulos Renais Proximais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/antagonistas & inibidores , Nitrilas/farmacologia , Canais de Potássio/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia , Sulfonas/farmacologia , Receptores Toll-Like/agonistas , Receptores Toll-Like/genética , Regulação para CimaRESUMO
Acute kidney injury is a common and severe clinical problem. Patients who develop acute kidney injury are at increased risk of death despite supportive measures such as hemodialysis. Research in recent years has shown that tissue inflammation is central to the pathogenesis of renal injury, even after nonimmune insults such as ischemia/reperfusion and toxins. Examination of clinical samples and preclinical models has shown that activation of the complement system is a critical cause of acute kidney injury. Furthermore, complement activation within the injured kidney is a proximal trigger of many downstream inflammatory events within the renal parenchyma that exacerbate injury to the kidney. Complement activation also may account for the systemic inflammatory events that contribute to remote organ injury and patient mortality. Complement inhibitory drugs have now entered clinical use and may provide an important new therapeutic approach for patients suffering from, or at high risk of developing, acute kidney injury.