Peptidylarginine Deiminase Inhibition by Cl-Amidine Improves Survival and Attenuates Kidney Injury in a Model of Endotoxic Shock in Rabbits

Ali Siddiqui; Aaron M. Williams; Umar F. Bhatti; Ben Biesterveld; Yuzi Tian; Zhenyu Wu; Baoling Liu; Yongqing Li; Hasan Badre Alam

doi:10.1016/j.jamcollsurg.2020.07.673

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

10.21203/rs.2.16993/v1 ◽

2019 ◽

Author(s):

Nara Aline Costa ◽

Bertha Furlan Polegato ◽

Amanda Gomes Pereira ◽

Rodrigo Velloni da Silva Bastos ◽

Sérgio Alberto Rupp de Paiva ◽

...

Keyword(s):

Septic Shock ◽

Acute Kidney Injury ◽

Renal Replacement Therapy ◽

Kidney Injury ◽

Peptidylarginine Deiminase ◽

Plasma Urea ◽

Blood Samples ◽

Icu Stay ◽

Plasma Urea Concentration ◽

Its Polymorphism

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

Revista da Associação Médica Brasileira ◽

10.1590/1806-9282.66.11.1515 ◽

2020 ◽

Vol 66 (11) ◽

pp. 1515-1520

Author(s):

Nara Aline Costa ◽

Bertha Furlan Polegato ◽

Amanda Gomes Pereira ◽

Sérgio Alberto Rupp de Paiva ◽

Ana Lúcia Gut ◽

...

Keyword(s):

Septic Shock ◽

Acute Kidney Injury ◽

Renal Replacement Therapy ◽

Replacement Therapy ◽

Kidney Injury ◽

Peptidylarginine Deiminase ◽

Plasma Urea ◽

Blood Samples ◽

Peptidylarginine Deiminase 4 ◽

Plasma Urea Concentration

SUMMARY BACKGROUND: The aim of this study is to evaluate the peptidylarginine deiminase 4 (PAD 4) concentration and PADI4 polymorphisms as predictors of acute kidney injury (AKI) development, the need for renal replacement therapy (RRT), and mortality in patients with septic shock. METHODS: We included all individuals aged ≥ 18 years, with a 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 PADI4 polymorphism (rs11203367) and (rs874881). Patients were monitored during their ICU stay and the development of SAKI was evaluated. Among the patients in whom SAKI developed, mortality and the need for RRT were also evaluated. RESULTS: There were 99 patients, 51.5% of whom developed SAKI and of these, 21.5% needed RRT and 80% died in the ICU. 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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HO-1/PINK1 Regulated Mitochondrial Fusion/Fission to Inhibit Pyroptosis and Attenuate Septic Acute Kidney Injury

BioMed Research International ◽

10.1155/2020/2148706 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Hai-Bo Li ◽

Xi-Zhe Zhang ◽

Yi Sun ◽

Qi Zhou ◽

Jian-Nan Song ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Renal Function ◽

Inflammatory Response ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Endotoxic Shock ◽

Kidney Injury ◽

Treated Group ◽

Mitochondrial Fusion

Background. Endotoxin-associated acute kidney injury (AKI), a disease characterized by marked oxidative stress and inflammation disease, is a major cause of mortality in critically ill patients. Mitochondrial fission and pyroptosis often occur in AKI. However, the underlying biological pathways involved in endotoxin AKI remain poorly understood, especially those related to mitochondrial dynamics equilibrium disregulation and pyroptosis. Previous studies suggest that heme oxygenase- (HO-) 1 confers cytoprotection against AKI during endotoxic shock, and PTEN-induced putative kinase 1 (PINK1) takes part in mitochondrial dysfunction. Thus, in this study, we examine the roles of HO-1/PINK1 in maintaining the dynamic process of mitochondrial fusion/fission to inhibit pyroptosis and mitigate acute kidney injury in rats exposed to endotoxin. Methods. An endotoxin-associated AKI model induced by lipopolysaccharide (LPS) was used in our study. Wild-type (WT) rats and PINK1 knockout (PINK1KO) rats, respectively, were divided into four groups: the control, LPS, Znpp+LPS, and Hemin+LPS groups. Rats were sacrificed 6 h after intraperitoneal injecting LPS to assess renal function, oxidative stress, and inflammation by plasma. Mitochondrial dynamics, morphology, and pyroptosis were evaluated by histological examinations. Results. In the rats with LPS-induced endotoxemia, the expression of HO-1 and PINK1 were upregulated at both mRNA and protein levels. These rats also exhibited inflammatory response, oxidative stress, mitochondrial fission, pyroptosis, and decreased renal function. After upregulating HO-1 in normal rats, pyroptosis was inhibited; mitochondrial fission and inflammatory response to oxidative stress were decreased; and the renal function was improved. The effects were reversed by adding Znpp (a type of HO-1 inhibitor). Finally, after PINK1 knockout, there is no statistical difference in the LPS-treated group and Hemin or Znpp pretreated group. Conclusions. HO-1 inhibits inflammation response and oxidative stress and regulates mitochondria fusion/fission to inhibit pyroptosis, which can alleviate endotoxin-induced AKI by PINK1.

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