Peroxiredoxin 1 aggravates acute kidney injury by promoting inflammation through Mincle/Syk/NF-κB signaling

Abstract

Damage-associated molecular patterns (DAMPs) are a cause of acute kidney injury (AKI). Our knowledge of these DAMPs remains incomplete. Here, we report serum peroxiredoxin 1 (Prdx1) as a novel DAMP for AKI. Lipopolysaccharide (LPS) and kidney ischemia/reperfusion injury instigated AKI with concurrent increases in serum Prdx1 and reductions of Prdx1 expression in kidney tubular epithelial cells. Genetic knockout of Prdx1 or use of a Prdx1–neutralizing antibody protected mice from AKI and this protection was impaired by introduction of recombinant Prdx1 (rPrdx1). Mechanistically, lipopolysaccharide increased serum and kidney proinflammatory cytokines, macrophage infiltration, and the content of M1 macrophages. All these events were suppressed in Prdx1-/- mice and renewed upon introduction of rPrdx1. In primary peritoneal macrophages, rPrdx1 induced M1 polarization, activated macrophage-inducible C-type lectin (Mincle) signaling, and enhanced proinflammatory cytokine production. Prdx1 interacted with Mincle to initiate acute kidney inflammation. Of note, rPrdx1 upregulated Mincle and the spleen tyrosine kinase Syk system in the primary peritoneal macrophages, while knockdown of Mincle abolished the increase in activated Syk. Additionally, rPrdx1 treatment enhanced the downstream events of Syk, including transcription factor NF-κB signaling pathways. Furthermore, serum Prdx1 was found to be increased in patients with AKI; the increase of which was associated with kidney function decline and inflammatory biomarkers in patient serum. Thus, kidney-derived serum Prdx1 contributes to AKI at least in part by activating Mincle signaling and downstream pathways. Damage-associated molecular patterns (DAMPs) are a cause of acute kidney injury (AKI). Our knowledge of these DAMPs remains incomplete. Here, we report serum peroxiredoxin 1 (Prdx1) as a novel DAMP for AKI. Lipopolysaccharide (LPS) and kidney ischemia/reperfusion injury instigated AKI with concurrent increases in serum Prdx1 and reductions of Prdx1 expression in kidney tubular epithelial cells. Genetic knockout of Prdx1 or use of a Prdx1–neutralizing antibody protected mice from AKI and this protection was impaired by introduction of recombinant Prdx1 (rPrdx1). Mechanistically, lipopolysaccharide increased serum and kidney proinflammatory cytokines, macrophage infiltration, and the content of M1 macrophages. All these events were suppressed in Prdx1-/- mice and renewed upon introduction of rPrdx1. In primary peritoneal macrophages, rPrdx1 induced M1 polarization, activated macrophage-inducible C-type lectin (Mincle) signaling, and enhanced proinflammatory cytokine production. Prdx1 interacted with Mincle to initiate acute kidney inflammation. Of note, rPrdx1 upregulated Mincle and the spleen tyrosine kinase Syk system in the primary peritoneal macrophages, while knockdown of Mincle abolished the increase in activated Syk. Additionally, rPrdx1 treatment enhanced the downstream events of Syk, including transcription factor NF-κB signaling pathways. Furthermore, serum Prdx1 was found to be increased in patients with AKI; the increase of which was associated with kidney function decline and inflammatory biomarkers in patient serum. Thus, kidney-derived serum Prdx1 contributes to AKI at least in part by activating Mincle signaling and downstream pathways. Translational StatementAcute kidney injury (AKI) remains a major health issue. As a disease characterized by inflammatory response, AKI is exacerbated by damage-associated molecular patterns (DAMPs). Advances in our understanding of AKI-associated DAMPs are a vital aspect of improving the clinical management of AKI. We here have demonstrated serum peroxiredoxin 1 (Prdx1) as a novel DAMP for AKI. Although serum Prdx1 contributes to AKI, reduction of Prdx1 in the circulation, using a Prdx1-neutralizing antibody or via genetic knockout of Prdx1, protects mice from AKI. This study reveals the therapeutic potential of managing AKI via reduction of circulating Prdx1. Acute kidney injury (AKI) remains a major health issue. As a disease characterized by inflammatory response, AKI is exacerbated by damage-associated molecular patterns (DAMPs). Advances in our understanding of AKI-associated DAMPs are a vital aspect of improving the clinical management of AKI. We here have demonstrated serum peroxiredoxin 1 (Prdx1) as a novel DAMP for AKI. Although serum Prdx1 contributes to AKI, reduction of Prdx1 in the circulation, using a Prdx1-neutralizing antibody or via genetic knockout of Prdx1, protects mice from AKI. This study reveals the therapeutic potential of managing AKI via reduction of circulating Prdx1. Acute kidney injury (AKI) is a major health issue, with 13.3 million annual cases and 1.7 million mortalities worldwide every year.1Mehta R.L. Cerdá J. Burdmann E.A. et al.International Society of Nephrology's 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology.Lancet. 2015; 385: 2616-2643Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar The disease is characterized by a rapid loss of kidney function.2Ronco C. Bellomo R. Kellum J.A. Acute kidney injury.Lancet. 2019; 394: 1949-1964Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar AKI develops in 10%–15% of hospitalized patients, and up to 50% of patients are admitted to the intensive care unit, with a morbidity rate reaching 5.7%.3Moore P.K. Hsu R.K. Liu K.D. Management of acute kidney injury: core curriculum 2018.Am J Kidney Dis. 2018; 72: 136-148Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 4Al-Jaghbeer M. 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D. et al.Circulating is a novel damage-associated molecular pattern and acute injury via 2019; PubMed Scopus Google Scholar In the DAMP of serum Prdx1 in tissue injury, we report circulating Prdx1 as a novel DAMP for AKI, at least in part by activating macrophage-inducible C-type lectin (Mincle) of serum Prdx1 mice from AKI. This reveals therapeutic potential of managing AKI via reduction of circulating Prdx1. were by the of for this study was from the and the AKI and kidney from and AKI patients were from The of AKI was to the Kidney J.A. and management of acute kidney injury: a PubMed Scopus Google Scholar Prdx1 knockout mice were using the as Y. S. D. et al.Circulating is a novel damage-associated molecular pattern and acute injury via 2019; PubMed Scopus Google Scholar and to were All and were by the for of lipopolysaccharide AKI was of at a of mice were or renal for AKI was as A. et in and expression in mice with acute kidney 2020; PubMed Scopus Google Scholar renal were for using and the were to was at the by using a were or a macrophage and were mice The were to and the of the AKI was induced by as and primary peritoneal cells with or Mincle knockdown were the The mice were macrophage The of macrophage was by the of by and All are as was with The was for and were using of by a were using the of were for are in the a potential of circulating Prdx1 in AKI, we induced AKI in mice using is the cause of AKI, which is or using in C. A. et to is of acute kidney injury in Int. 2014; Full Text Full Text PDF PubMed Scopus Google et acute kidney injury.Kidney Int. Full Text Full Text PDF PubMed Scopus Google Scholar of in kidney injury at with at by increases in with tubular epithelial cell loss of tubular and tubular injury were at at was associated with in kidney function and was a of serum Prdx1 in mice with AKI at which was increased at support the of serum Prdx1 in mice with AKI, we induced AKI using renal AKI in with were demonstrated and which are to the in kidney injury with AKI were associated with kidney function decline and As in mice with AKI induced by a increase in serum Prdx1 in AKI mice of AKI in the the acute of kidney injury et is the primary of and acute kidney injury.Kidney Int. 2020; 97: Full Text Full Text PDF PubMed Scopus Google Scholar, A. M. et renal inflammation ischemia Scopus Google Scholar, D. M. M. et of kinase protects kidney injury.Kidney Int. Full Text Full Text PDF PubMed Scopus Google Scholar our for the acute we a in kidney injury from the increase in serum Prdx1 in AKI in AKI. The of serum Prdx1 in AKI caused by and circulating Prdx1 is to AKI. the of circulating Prdx1 to AKI, we the of Prdx1 AKI using Prdx1 knockout mice Y. S. D. et al.Circulating is a novel damage-associated molecular pattern and acute injury via 2019; PubMed Scopus Google Scholar Prdx1 tubular injury with of kidney function in mice with protection of AKI with of kidney function also in mice with this we induced AKI in mice with of recombinant Prdx1 (rPrdx1). of mice to kidney injury with kidney function decline in response to treatment The of rPrdx1 was the serum Prdx1 in AKI serum Prdx1 of was at in AKI mice of for mice at of rPrdx1 at is the of serum Prdx1 in AKI rPrdx1 increased the of mice to kidney injury caused by for a role of circulating Prdx1 in AKI, we the of a Prdx1-neutralizing antibody AKI. with the Prdx1-neutralizing antibody protection from kidney and and of kidney the antibody of kidney and and kidney function decline caused by in mice we a circulating Prdx1 AKI. 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Griffin M.D. McKay D.B. et al.Inflammation in AKI: current understanding, key questions, and knowledge gaps.J Am Soc Nephrol. 2016; 27: 371-379Crossref PubMed Scopus (341) Google Scholar Our a in which kidney injury leads to the release of a of DAMPs, including the in acute renal at least in part via activation of Mincle signaling, by the of inflammatory and the subsequent AKI is to a of Prdx1 be to AKI in we a of serum Prdx1 in AKI to AKI. Thus, a is a of serum Prdx1 to AKI in response to kidney is to the of high and of serum Prdx1 AKI caused by and Our a renal of serum Prdx1 in AKI. 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Bellomo R. et al.Acute renal failure in critically ill patients: a multinational, multicenter study.JAMA. 2005; 294: 813-818Crossref PubMed Scopus (3211) Google Scholar The potential of serum Prdx1 from to AKI the of in the and of Additionally, the remains serum Prdx1 is from the kidney the which is to be a of AKI, is to be from et is the primary of and acute kidney injury.Kidney Int. 2020; 97: Full Text Full Text PDF PubMed Scopus Google Scholar this the for in AKI and acute by Prdx1 from the therapeutic is by our from the of AKI via the of Prdx1 in the kidney this and the of in AKI. include DAMPs associated with AKI, as high-mobility group box-1 H. J. P. et contributes to kidney ischemia Am Soc Nephrol. 2010; PubMed Scopus Google L. Chen of in acute kidney Scopus Google Scholar heat shock A. D. F. et shock is in and in for Am Soc Nephrol. 2005; PubMed Scopus Google Scholar and proinflammatory and F. Yin J. 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