Circulating levels of advanced glycation end products (AGE) and interleukin-6 (IL-6) are independent determinants of serum asymmetric dimethylarginine (ADMA) levels in patients with septic shock
Abstract
There is a growing body of evidence that nitric oxide (NO) excess plays a central role in the pathogenesis of hypotension and organ failure in patients with septic shock. In addition, recently, asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, has been shown to contribute to the regulation of vascular tone via modulation of NO generation in vivo. However, the kinetics and regulation of serum levels of ADMA in patients with septic shock are largely unknown. Since high mobility group box 1 (HMGB1)-receptor for advanced end products (RAGE) axis is supposed to be involved in the lethality in septic shock, we examined the correlations among serum levels of ADMA, endotoxin, interleukin-6 (IL-6), soluble form of RAGE (sRAGE) and RAGE ligands such as HMGB1 and advanced glycation end products (AGE) in septic shock patients. Fifteen septic shock patients (10 males and 15 females, mean age: 70.1+/-8.5 years) and fifteen age- and sex-matched healthy volunteers were included in this study. The criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference were used for diagnosis of septic shock. All the subjects underwent a complete history and physical examination, determination of blood chemistries, including serum levels of ADMA, endotoxin, IL-6, HMGB1, AGE and sRAGE. Linear and multiple stepwise regression analysis were performed for the determinants of serum levels of ADMA. Serum levels of ADMA were significantly higher than those in healthy volunteers (0.98+/-0.21nmol/mL vs. 0.30+/-0.05nmol/mL, p<0.0001). In univariate analysis, creatinine (p<0.005), endotoxin (p<0.001), IL-6 (p<0.001), HMGB1 (p<0.001), AGE (p<0.001) and sRAGE (p<0.001) were significantly associated with serum ADMA levels. After performing multivariate stepwise regression analyses, IL-6 (p=0.001), AGE (p=0.002) and creatinine (p=0.013) still remained significant independently. The present study is the first demonstration that ADMA levels were significantly elevated in patients with septic shock and that serum IL-6, AGE and creatinine levels were independent determinants of ADMA in these patients. Given the harmful effects of NO excess in septic shock, ADMA levels may be increased as a counter-system against inflammation and oxidative stress in this life-threatening disorder.
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The RAGE ligand HMGB1 plays a causal role in renal inflammation by enhancing ERK1/2, TNF-α, IL-6, and MCP-1, leading to nephropathy and chronic kidney disease.
“The RAGE ligand HMGB1 also plays a causal role in renal inflammation by enhancing ERK1/2, TNF-α, interleukin (IL)-6, and MCP-1, leading to nephropathy and chronic kidney disease74,75.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [74]
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- Authors
- Nakamura, T., Sato, E., Fujiwara, N., Kawagoe, Y., Suzuki, T., Ueda, Y., Yamada, S., Shoji, H., Takeuchi, M., Ueda, S., Matsui, T., Adachi, H., Okuda, S., & Yamagishi, S.-I.
- Affiliations
- Shinmatsudo Central General Hospital (JP)
- Dokkyo University (JP)
- Shino-Test Corporation (JP)
- Toray Medical Co., Ltd. (Japan) (JP)
- Hokuriku University (JP)
- Kurume University (JP)
- Corresponding author
- Yamagishi, Sho-ichi
- ORCID
- Venue
- Pharmacological Research
- Publisher
- Elsevier BV
- Published
- 2009-12
- Volume
- 60
- Issue
- 6
- Pages
- 515-518
- ISSN
- 1043-6618 (ISSN-L)
- OpenAlex
- W2058307492
- Cited by
- 46
- References
- 31
- Citations by year
- 2025: 2 · 2024: 1 · 2022: 1 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 1 · 2016: 5 · 2015: 2 · 2014: 3 · 2013: 3 · 2012: 8
- FWCI
- 3.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacological Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- septic shock, asymmetric dimethylarginine, advanced glycation end products, interleukin-6, HMGB1, RAGE, soluble RAGE, endotoxin, nitric oxide, nitric oxide synthase inhibition, creatinine, serum biomarkers, organ failure, hypotension, endotoxemia, oxidative stress, inflammation, endothelial dysfunction
- MeSH terms
- Aged, Arginine, Female, Humans, Male, Middle Aged, Shock, Septic, Biomarkers, Interleukin-6, Glycation End Products, Advanced
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