Abstract: FR-PO112
Circulating Peroxiredoxin 1 Is a Novel DAMP and Aggravates Acute Kidney Induced by Lipopolysaccharide via Promoting Inflammation
Session Information
- AKI: Mechanisms - Inflammation/Sepsis/Remote Injury
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Author
- Peng, Zhangzhe, Xiangya Hospital, Central South University, Changsha, HUBEI, China
Background
Damage-associated molecular patterns (DAMPs) are initiators of sterile inflammation, which is a key contributor to acute kidney injury (AKI). However, the current knowledge on those DAMPs that activate renal inflammation under AKI remains incomplete. Peroxiredoxin-1 (Prdx1) is a small protein in the Peroxiredoxins family, which are ubiquitous expressed enzymes reducing peroxide levels. Interestingly, recent studies indicated that intracellular Prdx1 could be released to extracellular space under certain stimuli and extracellular Prdx1 has been recently identified as a novel DAMP due to its pro-inflammatory property by binding to Toll-like receptor (TLR) 2/4.However, the crucial role of Prdx1 in AKI remains unclear.
Methods
Prdx1-deficient mice and patients with AKI were used to determine its function in AKI, potential mechanisms and human relevance.
Results
Intraperitoneal injection of lipopolysaccharide (LPS) elicited a progressive course of AKI in mice developed from 12 to 24-hour post injection along with renal inflammation evident by macrophage infiltration and upregulation of cytokines (IL-1β, IL-6); these alterations were concurrently occurred with a robust and progressive production of serum Prdx1. Similar observations were also obtained in ischemia-reperfusion-induced AKI mouse model in mice. Removal of the source of serum Prdx1 protected mice deficient in Prdx1 from LPS-induced liver injury, and decreased macrophage infiltration, IL-1β and IL-6 production. As a result, Prdx1-/- mice were strongly protected from LPS-induced death that was likely progressed from AKI. Additionally, intravenous re-introduction of recombinant Prdx1 (rPrdx1) in Prdx1-/- mice reversed or reduced all the above events, demonstrating an important contribution of circulating Prdx1 to AKI. rPrdx1 potently induced in primary macrophages the expression of pro-IL-1β, IL-6, TNF-α, and IL-1β through the NF-κB signaling as well as the NOD2 signaling. Furthermore, a significant elevation of serum Prdx1 was demonstrated in patients (n=31) with AKI; the elevation is associated with serum creatinine.
Conclusion
Our findings reveal a previously unrecognized detrimental role of prdx1 in LPS-induced renal inflammation and tissue damage and thereby identify novel and important therapeutic target for LPS-induced AKI.