A zebrafish model of infection-associated acute kidney injury.

Xiaoyan Wen,John A Kellum,David Emlet,Simon Watkins,Liyan Cui,Seth Morrisroe,Donald Maberry,Neil A Hukriede

doi:10.1152/ajprenal.00328.2017

Abstract

Sepsis-associated acute kidney injury (S-AKI) independently predicts mortality among critically ill patients. The role of innate immunity in this process is unclear, and there is an unmet need for S-AKI models to delineate the pathophysiological response. Mammals and zebrafish ( Danio rerio) share a conserved nephron structure and homologous innate immune systems, making the latter suitable for S-AKI research. We introduced Edwardsiella tarda to the zebrafish. Systemic E. tarda bacteremia resulted in sustained bacterial infection and dose-dependent mortality. A systemic immune reaction was characterized by increased mRNA expressions of il1b, tnfa, tgfb1a, and cxcl8-l1 ( P < 0.0001, P < 0.001, P < 0.001, and P < 0.01, respectively). Increase of host stress response genes ccnd1 and tp53 was observed at 24 h postinjection ( P < 0.0001 and P < 0.05, respectively). Moderate E. tarda infection induced zebrafish mortality of over 50% in larvae and 20% in adults, accompanied by pericardial edema in larvae and renal dysfunction in both larval and adult zebrafish. Expression of AKI markers insulin-like growth factor-binding protein-7 (IGFBP7), tissue inhibitor of metalloproteinases 2 (TIMP-2), and kidney injury molecule-1 (KIM-1) was found to be significantly increased in the septic animals at the transcription level ( P < 0.01, P < 0.05, and P < 0.05) and in nephric tubules compared with noninfected animals. In conclusion, we established a zebrafish model of S-AKI induced by E. tarda injection, with both larval and adult zebrafish showing nephron injury in the setting of infection.

Highlights

Sepsis is a systemic response triggered by infection
Microinjection with 300 colony-forming units (CFU) or more caused 60 –90% of larvae to die in a dose-dependent manner (P Ͻ 0.0001), whereas infection with 100 CFU did not result in significantly increased mortality compared with the PBS-injected controls
Our results showed increased expression of tissue inhibitor of metalloproteinases 2 (TIMP-2) and insulin-like growth factor-binding protein-7 (IGFBP7) in the pronephros at 48 h post-bacterial injection, with TIMP-2 predominantly found in the distal tubule and IGFBP7 in the proximal tubule

Summary

Introduction

Accounting for Ͻ10% of hospital admissions, sepsis contributes to half of all hospital deaths in the United States [30]. Multiple organ dysfunction syndrome is the main cause of death from sepsis, and renal dysfunction has been shown to contribute to this mortality [8]. Despite advances in modern medicine, the underlying mechanisms responsible for sepsisassociated acute kidney injury (S-AKI) are still unclear. The innate immune response is increasingly thought to play a major role in the pathophysiological changes responsible for S-AKI [13]. As the first line of defense, innate immunity is activated by host-pathogen interactions, including those between pattern recognition receptors (PRRs) and invading pathogen-associated molecular patterns (PAMPs) originating from exogenous bacteria and/or danger-associated molecular patterns (DAMPs), endogenous “alarmins” released from injured tissue. The interaction between kidney damage and dysfunction and their association with innate immune activity remain unclear

Methods

Results

Conclusion