Peptidylarginine deiminase 4 concentration, but not <i><scp>PADI</scp>4</i> polymorphisms, is associated with <scp>ICU</scp> mortality in septic shock patients

Costa, Nara Aline; Gut, Ana Lúcia; Azevedo, Paula Schmidt; Polegato, Bertha Furlan; Magalhães, Eloá Siqueira; Ishikawa, Larissa Lumi Watanabe; Bruder, Rita de Cassia Siqueira; Silva, Evelyn Aparecida da; Gonçalves, Renan Braga; Tanni, Suzana Erico; Rogero, Marcelo Macedo; Norde, Marina Maintinguer; Cunha, Natália Baraldi; Zornoff, Leonardo A. M.; Paiva, Sérgio Alberto Rupp de; Minicucci, Marcos F.

doi:10.1111/jcmm.13717

Cited by 23 publications

(17 citation statements)

References 21 publications

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“…Despite this, we did not observe a difference in the concentration of PAD4 between the individuals in whom AKI developed and those who died. This response is different from what we found in our previous study, with the same dataset, in which PAD4 concentration was associated with increased mortality in patients with septic shock [15]. This different performance of PAD4 as a biomarker suggests that PAD4 concentration is more important in sepsis than in AKI pathophysiology.…”

Section: Discussioncontrasting

confidence: 99%

“…Ham et al [14], demonstrated that PAD4 plays an important role in a model of renal ischemia-reperfusion injury by increasing tubular inflammatory response. Based on previous data published by our group, using the same dataset, higher PAD4 concentrations were associated with lower ICU survival in patients with septic shock [15].…”

Section: Introductionmentioning

confidence: 72%

“…In this work, we evaluated only two PADI4 polymorphisms (rs 11203367, rs 87481) and none of them had an association with the development of SAKI, or need for RRT and mortality. In addition, our previous study also showed in patients with septic shock that other PADI4 polymorphisms (rs 11203366, rs 2240340, rs 1748033) were not associated with mortality [15]. We also could not exclude the participation other PADI4 polymorphisms in SAKI development and outcomes.…”

Section: Discussionmentioning

confidence: 88%

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Evaluation of peptidylarginine deiminase 4 concentration and PADI4 polymorphisms in sepsis-induced acute kidney injury

Costa¹,

Polegato²,

Pereira³

et al. 2019

Preprint

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Background: The influence of PAD4 concentration and its polymorphisms in SAKI development are poorly evaluated. Thus, the aim of this study is to evaluate the PAD 4 concentration and PADI4 polymorphisms, as predictors of AKI development, need for renal replacement therapy (RRT), and mortality in patients with septic shock. Methods: We included all individuals aged ≥ 18 years, with the diagnosis of septic shock at ICU admission. Blood samples were taken within the first 24 hours of the patient’s admission to determine serum PAD4 concentration and its polymorphism PADI4 (rs11203367) and (rs874881). Patients were followed during their ICU stay and the development of SAKI was evaluated. Among the patients in whom SAKI developed, mortality and need for RRT were also evaluated. Results: 99 patients were included in the analysis. SAKI developed in approximately 51.5% of patients during the ICU stay; of these, 21.5% required RRT and 80% died. There was no difference between PAD4 concentration (p = 0.116) and its polymorphisms rs11203367 (p = 0.910) and rs874881 (p = 0.769) in patients in whom SAKI did or did not develop. However, PAD4 had a positive correlation with plasma urea concentration (r = 0.269 and p = 0.007) and creatinine (r = 0.284 and p = 0.004). The PAD4 concentration and PADI4 polymorphisms were also not associated with RRT and with mortality in patients with SAKI. Conclusion: PAD4 concentration and its polymorphisms were not associated with SAKI development, the need for RRT, or mortality in patients with septic shock. However, PAD4 concentrations were associated with creatinine and urea levels in these patients.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 88%

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Evaluation of peptidylarginine deiminase 4 concentration and PADI4 polymorphisms in sepsis-induced acute kidney injury

Costa¹,

Polegato²,

Pereira³

et al. 2019

Preprint

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“…Received: January 22, 2019 Revised: July 28, 2019 Accepted: September 4, 2019 Published: October 15, 2019 Brodziak et al, 2013;Chen et al, 2014;Costa et al, 2018;Grasberger et al, 2013;Haber et al, 2017;Han et al, 2013;Hosokawa, 2008;Huang et al, 2015;MacMicking, 2004;Mihara et al, 2016;Ozato et al, 2008;Toyonaga et al, 2015;van der Meer-van Kraaij et al, 2007;Wang et al, 2011;Williams et al, 2015;Yuan et al, 2018.…”

Section: Declaration Of Interestsmentioning

confidence: 99%

Polymorphic Immune Mechanisms Regulate Commensal Repertoire

et al. 2019

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“…This includes cancer, chronic, autoimmune and neurodegenerative diseases [ 19 , 20 , 23 ], CNS injury [ 24 , 25 , 26 ] and ageing [ 27 , 28 ]. Importantly, roles for PADs have been described in viral [ 29 , 30 , 31 ] and other pathogenic infections, including sepsis, endotoxemia [ 29 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ] and antibiotic resistance [ 39 ]. The roles for PADs in anti-viral responses include PAD-mediated neutrophil extracellular trap formation (NETosis), for example, in respiratory syncytial virus disease [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

Putative Roles for Peptidylarginine Deiminases in COVID-19

Arısan

Uysal-Onganer

Lange

2020

IJMS

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Peptidylarginine deiminases (PADs) are a family of calcium-regulated enzymes that are phylogenetically conserved and cause post-translational deimination/citrullination, contributing to protein moonlighting in health and disease. PADs are implicated in a range of inflammatory and autoimmune conditions, in the regulation of extracellular vesicle (EV) release, and their roles in infection and immunomodulation are known to some extent, including in viral infections. In the current study we describe putative roles for PADs in COVID-19, based on in silico analysis of BioProject transcriptome data (PRJNA615032 BioProject), including lung biopsies from healthy volunteers and SARS-CoV-2-infected patients, as well as SARS-CoV-2-infected, and mock human bronchial epithelial NHBE and adenocarcinoma alveolar basal epithelial A549 cell lines. In addition, BioProject Data PRJNA631753, analysing patients tissue biopsy data (n = 5), was utilised. We report a high individual variation observed for all PADI isozymes in the patients’ tissue biopsies, including lung, in response to SARS-CoV-2 infection, while PADI2 and PADI4 mRNA showed most variability in lung tissue specifically. The other tissues assessed were heart, kidney, marrow, bowel, jejunum, skin and fat, which all varied with respect to mRNA levels for the different PADI isozymes. In vitro lung epithelial and adenocarcinoma alveolar cell models revealed that PADI1, PADI2 and PADI4 mRNA levels were elevated, but PADI3 and PADI6 mRNA levels were reduced in SARS-CoV-2-infected NHBE cells. In A549 cells, PADI2 mRNA was elevated, PADI3 and PADI6 mRNA was downregulated, and no effect was observed on the PADI4 or PADI6 mRNA levels in infected cells, compared with control mock cells. Our findings indicate a link between PADI expression changes, including modulation of PADI2 and PADI4, particularly in lung tissue, in response to SARS-CoV-2 infection. PADI isozyme 1–6 expression in other organ biopsies also reveals putative links to COVID-19 symptoms, including vascular, cardiac and cutaneous responses, kidney injury and stroke. KEGG and GO pathway analysis furthermore identified links between PADs and inflammatory pathways, in particular between PAD4 and viral infections, as well as identifying links for PADs with a range of comorbidities. The analysis presented here highlights roles for PADs in-host responses to SARS-CoV-2, and their potential as therapeutic targets in COVID-19.

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Peptidylarginine deiminase 4 concentration, but not PADI4 polymorphisms, is associated with ICU mortality in septic shock patients

Cited by 23 publications

References 21 publications

Evaluation of peptidylarginine deiminase 4 concentration and PADI4 polymorphisms in sepsis-induced acute kidney injury

Evaluation of peptidylarginine deiminase 4 concentration and PADI4 polymorphisms in sepsis-induced acute kidney injury

Polymorphic Immune Mechanisms Regulate Commensal Repertoire

Putative Roles for Peptidylarginine Deiminases in COVID-19

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