Characterization of histidine-rich glycoprotein (HRG) production under the experimental pathological conditions

[Speaker] Kiyoshi Teshigawara:1
[Co-author] Atsuko Niwa:2, Hidenori Wake:1, Dengli Wang:1, Keyue Liu:1, Shuji Mori:3, Hideo Takahashi:2, Masahiro Nishibori:1
1:Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan, 2:Department of Pharmacology, Faculty of Medicine, Kinki University, Japan, 3:School of Pharmacy, Shujitsu University, Japan

Background: Histidine-rich glycoprotein (HRG) is a plasma glycoprotein of 75 kDa, which contains multiple tandem repeats with a GHHPH motif in carboxyl-terminal side. HRG is secreted from liver and circulating in bloodstream at high concentration of 1.0 uM. Plasma HRG interacts with many ligands, such as divalent metal ions, haem, heparin, plasminogen, IgG and so on. Recently, we reported that HRG is associated with regulation of blood vascular function in septic pathophysiology. In sepsis rodent model induced by cecal ligation and puncture (CLP), the plasma HRG levels significantly decreased and supplementary HRG administration dramatically improved the survival of the CLP mice. The therapeutic efficacy is attributed to strong inhibition of neutrophil activation and protection of vascular endothelial cells in septic condition. Therefore, HRG might be considered to have multifunctional properties against progression of various inflammatory diseases, whereas little is known about the regulatory mechanisms of HRG expression in the liver.
Methods: Inflammatory rat models were prepared to evaluate the alteration of HRG production in the liver. These included CLP-treated stroke-prone spontaneously hypertensive rats (CLP-SHRSP rats) as a chronic/acute inflammatory model and streptozotocin-induced diabetic rats (STZ rats) as a chronic inflammatory model. Besides evaluating HRG production in the liver, HRG protein was purified from plasma of CLP-SHRSP rats at an early phase of sepsis using Ni-NTA affinity chromatography. Sepsis condition-specific proteins, which were recovered together with HRG from chromatography column in the purification process, were identified as novel candidates of HRG-associated protein using mass spectrometry analysis.
Results: HRG production was increased with regard to the liver expression level in both condition of SHRSP-hypertensive and STZ-induced hyperglycemia. Plasma levels of HRG were also increased in both models. Enhanced HRG production in SHRSP rats was markedly reduced by CLP-treated sepsis condition. Each of HRG-associated proteins identified by using mass spectrometry analysis was known to be involved in inflammation pathology.
Conclusion: These results suggest that HRG production in the liver is regulated actively to protect against inflammatory impairments in various pathological conditions.

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