Early treatment with C-reactive protein-derived peptide reduces septic acute kidney injury in mice via controlled activation of kidney macrophages

Author:

Ito Seigo1ORCID,Goto Hiroyasu1,Tanoue Keiko1,Koiwai Kazuki2,Ishikiriyama Takuya2,Kearney Bradley M2ORCID,Mori Kazuma2,Nakashima Masahiro2ORCID,Nakashima Hiroyuki2,Kumagai Hiroo1,Seki Shuhji2,Kinoshita Manabu2ORCID,Oshima Naoki1

Affiliation:

1. Department of Nephrology and Endocrinology, National Defense Medical College , 3-2 Namiki, Tokorozawa, Saitama 359-8513 , Japan

2. Department of Immunology and Microbiology, National Defense Medical College , 3-2 Namiki, Tokorozawa, Saitama 359-8513 , Japan

Abstract

AbstractThe mortality rate for acute kidney injury (AKI) due to sepsis remains high, and effective therapies based on its pathogenesis remain elusive. Macrophages are crucial for clearing bacteria from vital organs, including the kidney, under septic conditions. Excessive macrophage activation results in organ injury. C-reactive protein (CRP) peptide (174-185), a functional product of proteolyzed CRP in vivo, effectively activates macrophages. We investigated the therapeutic efficacy of synthetic CRP peptide on septic AKI, focusing on effects on kidney macrophages. Mice underwent cecal ligation and puncture (CLP) to induce septic AKI and were intraperitoneally administered 20 mg/kg of synthetic CRP peptide 1 h post-CLP. Early CRP peptide treatment improved AKI while still clearing infection. Ly6C-negative kidney tissue-resident macrophages did not significantly increase at 3 h after CLP, while Ly6C-positive monocyte-derived macrophages significantly accumulated in the kidney 3 h post-CLP. CRP peptide augmented the phagocytic ROS production in both subtypes of kidney macrophage at 3 h. Interestingly, both subtypes of macrophage increased ROS production 24 h post-CLP compared to the control group, while CRP peptide treatment maintained ROS production at the same level seen 3 h post-CLP. Although bacterium-phagocytic kidney macrophages produced TNF-α, CRP peptide reduced bacterial propagation and tissue TNF-α levels in the septic kidney at 24 h. Although both subsets of kidney macrophages showed populations of M1 at 24 h post-CLP, CRP peptide therapy skewed the macrophages population toward M2 at 24 h. CRP peptide alleviated murine septic AKI via the controlled activation of kidney macrophages and is an excellent candidate for future human therapeutic studies.

Funder

National Defense Medical College

JSPS KAKENHI

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Immunology,Immunology and Allergy

Reference50 articles.

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