Dipeptidase-1 governs renal inflammation during ischemia reperfusion injury

Lau, Arthur; Rahn, Jennifer J.; Chappellaz, Mona; Chung, Hyunsoo; Benediktsson, Hallgrímur; Bihan, Dominique; Mäßenhausen, Anne von; Linkermann, Andreas; Jenne, Craig N.; Robbins, Stephen M.; Senger, Donna L.; Lewis, Ian A.; Chun, Justin; Muruve, Daniel A.

doi:10.1126/sciadv.abm0142

Cited by 48 publications

(22 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DPEP1 is highly expressed in proximal tubular cells and peritubular capillaries of the normal kidney ( Choudhury et al, 2019 ; Nitanai et al, 2002 ). Lau et al (2022) reported that DPEP1 deficiency could block neutrophil adhesion to peritubular capillaries and reduce inflammatory monocyte recruitment to the kidney after ischemia reperfusion injury, and DPEP1 itself could be a potential therapeutic target for acute kidney injury. DPEP1 has also been implicated in several types of cancers.…”

Section: Discussionmentioning

confidence: 99%

A novel lipid metabolism gene signature for clear cell renal cell carcinoma using integrated bioinformatics analysis

Zhu²,

Cheng³

et al. 2023

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Background: Clear cell renal cell carcinoma (ccRCC), which is the most prevalent type of renal cell carcinoma, has a high mortality rate. Lipid metabolism reprogramming is a hallmark of ccRCC progression, but its specific mechanism remains unclear. Here, the relationship between dysregulated lipid metabolism genes (LMGs) and ccRCC progression was investigated.Methods: The ccRCC transcriptome data and patients’ clinical traits were obtained from several databases. A list of LMGs was selected, differentially expressed gene screening performed to detect differential LMGs, survival analysis performed, a prognostic model established, and immune landscape evaluated using the CIBERSORT algorithm. Gene Set Variation Analysis and Gene set enrichment analysis were conducted to explore the mechanism by which LMGs affect ccRCC progression. Single-cell RNA-sequencing data were obtained from relevant datasets. Immunohistochemistry and RT-PCR were used to validate the expression of prognostic LMGs.Results: Seventy-one differential LMGs were identified between ccRCC and control samples, and a novel risk score model established comprising 11 LMGs (ABCB4, DPEP1, IL4I1, ENO2, PLD4, CEL, HSD11B2, ACADSB, ELOVL2, LPA, and PIK3R6); this risk model could predict ccRCC survival. The high-risk group had worse prognoses and higher immune pathway activation and cancer development.Conclusion: Our results showed that this prognostic model can affect ccRCC progression.

show abstract

Section: Discussionmentioning

confidence: 99%

A novel lipid metabolism gene signature for clear cell renal cell carcinoma using integrated bioinformatics analysis

Zhu²,

Cheng³

et al. 2023

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…35 Recent articles have shown that dexamethasone and prednisolone increase the dipeptidase-1 levels during renal I/R injury, which leads to glutathione depletion and ferroptosis. 36,37 These studies suggest that ferroptosis may contribute to the adverse effects of glucocorticoids and that glucocorticoids, combined with interventions targeting Alox15, can achieve better clinical outcomes.…”

Section: Time Window Of Cardiomyocyte Death During I/r Injurymentioning

confidence: 99%

Alox15/15-HpETE Aggravates Myocardial Ischemia-Reperfusion Injury by Promoting Cardiomyocyte Ferroptosis

et al. 2023

View full text Add to dashboard Cite

BACKGROUND: Myocardial ischemia-reperfusion (I/R) injury causes cardiac dysfunction to myocardial cell loss and fibrosis. Prevention of cell death is important to protect cardiac function after I/R injury. The process of reperfusion can lead to multiple types of cardiomyocyte death, including necrosis, apoptosis, autophagy, and ferroptosis. However, the time point at which the various modes of cell death occur after reperfusion injury and the mechanisms underlying ferroptosis regulation in cardiomyocytes are still unclear. METHODS: Using a left anterior descending coronary artery ligation mouse model, we sought to investigate the time point at which the various modes of cell death occur after reperfusion injury. To discover the key molecules involved in cardiomyocyte ferroptosis, we performed a metabolomics study. Loss/gain-of-function approaches were used to understand the role of 15-lipoxygenase (Alox15) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α) in myocardial I/R injury. RESULTS: We found that apoptosis and necrosis occurred in the early phase of I/R injury, and that ferroptosis was the predominant form of cell death during the prolonged reperfusion. Metabolomic profiling of eicosanoids revealed that Alox15 metabolites accumulated in ferroptotic cardiomyocytes. We demonstrated that Alox15 expression was specifically increased in the injured area of the left ventricle below the suture and colocalized with cardiomyocytes. Furthermore, myocardial-specific knockout of Alox15 in mice alleviated I/R injury and restored cardiac function. 15-Hydroperoxyeicosatetraenoic acid (15-HpETE), an intermediate metabolite derived from arachidonic acid by Alox15, was identified as a trigger for cardiomyocyte ferroptosis. We explored the mechanism underlying its effects and found that 15-HpETE promoted the binding of Pgc1α to the ubiquitin ligase ring finger protein 34, leading to its ubiquitin-dependent degradation. Consequently, attenuated mitochondrial biogenesis and abnormal mitochondrial morphology were observed. ML351, a specific inhibitor of Alox15, increased the protein level of Pgc1α, inhibited cardiomyocyte ferroptosis, protected the injured myocardium, and caused cardiac function recovery. CONCLUSIONS: Together, our results established that Alox15/15-HpETE–mediated cardiomyocyte ferroptosis plays an important role in prolonged I/R injury.

show abstract

“…Several enriched pathways were screened out through KEGG and GO analyses of differentially expressed genes and genes with different m6A peaks. Inflammatory response is known to play a vital role in AKI, and several experimental studies have demonstrated that I/R-induced AKI was abrogated when inflammation was blocked 8 , 37 , 38 . Recent studies have identified an important role of ALKBH5 in inflammation and immune cell regulation 39 – 41 .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment

Chen

Yang

et al. 2023

Nat Commun

View full text Add to dashboard Cite

Ischemia reperfusion injury (IRI) is a common cause of acute kidney injury (AKI). The role of N6-methyladenosine (m6A) modification in AKI remains unclear. Here, we characterize the role of AlkB homolog 5 (ALKBH5) and m6A modification in an I/R-induced renal injury model in male mice. Alkbh5-knockout mice exhibit milder pathological damage and better renal function than wild-type mice post-IRI, whereas Alkbh5-knockin mice show contrary results. Also conditional knockout of Alkbh5 in the tubular epithelial cells alleviates I/R-induced AKI and fibrosis. CCL28 is identified as a target of ALKBH5. Furthermore, Ccl28 mRNA stability increases with Alkbh5 deficiency, mediating by the binding of insulin-like growth factor 2 binding protein 2. Treg recruitment is upregulated and inflammatory cells are inhibited by the increased CCL28 level in IRI-Alkbh5fl/flKspCre mice. The ALKBH5 inhibitor IOX1 exhibits protective effects against I/R-induced AKI. In summary, inhibition of ALKBH5 promotes the m6A modifications of Ccl28 mRNA, enhancing its stability, and regulating the Treg/inflammatory cell axis. ALKBH5 and this axis is a potential AKI treatment target.

show abstract

Dipeptidase-1 governs renal inflammation during ischemia reperfusion injury

Cited by 48 publications

References 42 publications

A novel lipid metabolism gene signature for clear cell renal cell carcinoma using integrated bioinformatics analysis

A novel lipid metabolism gene signature for clear cell renal cell carcinoma using integrated bioinformatics analysis

Alox15/15-HpETE Aggravates Myocardial Ischemia-Reperfusion Injury by Promoting Cardiomyocyte Ferroptosis

Inhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment

Contact Info

Product

Resources

About