Sepsis-induced organ failure is mediated by different pathways in the kidney and liver: acute renal failure is dependent on MyD88 but not renal cell apoptosis

Kidney International
J W DearRobert A Star

Abstract

Toll-like receptors (TLRs) are important in sepsis. Myeloid differentiation factor 88 (MyD88) is a key molecule involved in signal transduction by multiple TLRs. The objective of this study was to investigate the contribution of TLR4 and MyD88 to acute renal failure (ARF) induced by polymicrobial sepsis. Liver dysfunction and apoptosis in the spleen contribute to sepsis severity after cecal ligation and puncture (CLP). Therefore, we also investigated liver injury and splenic apoptosis. We used a mouse model of sepsis-induced ARF using CLP to generate polymicrobial sepsis. Despite fluid and antibiotic resuscitation the mice developed multi-organ failure, including ARF, which resembles human sepsis. We investigated the role of the TLR4 receptor by comparing C3H/HeJ mice (which lack TLR4) with C3H/He0UJ normal controls. The role of MyD88 was investigated by comparing MyD88 knockout mice (MyD88(-/-)) with wild-type controls. Following CLP, mice lacking TLR4 and wild-type mice both developed comparable ARF. However, MyD88(-/-) mice did not develop ARF compared to wild-type controls. In contrast, MyD88(-/-) mice developed liver injury comparable to wild type. After CLP, MyD88(-/-) mice had significantly reduced apoptosis in the splee...Continue Reading

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