Blockade of CD38 diminishes lipopolysaccharide-induced macrophage classical activation and acute kidney injury involving NF-κB signaling suppression

Bingyan Shu; Ye Feng; Yuan Gui; Qingmiao Lu; Wei Wei; Xian Xue; Xiaoli Sun; Weichun He; Junwei Yang; Chunsun Dai

doi:10.1016/j.cellsig.2017.10.014

Blockade of CD38 diminishes lipopolysaccharide-induced macrophage classical activation and acute kidney injury involving NF-κB signaling suppression

Cell Signal. 2018 Jan:42:249-258. doi: 10.1016/j.cellsig.2017.10.014. Epub 2017 Nov 12.

Authors

Bingyan Shu¹, Ye Feng¹, Yuan Gui¹, Qingmiao Lu¹, Wei Wei¹, Xian Xue¹, Xiaoli Sun¹, Weichun He¹, Junwei Yang¹, Chunsun Dai²

Affiliations

¹ Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu, PR China.
² Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu, PR China. Electronic address: [email protected].

PMID: 29080804
DOI: 10.1016/j.cellsig.2017.10.014

Abstract

The CD38, possessing ADP-ribosyl cyclase (ADPR-cyclase) and cyclic ADP-ribose hydrolase (cADPR-hydrolase), is able to regulate a variety of cellular activities. However, the role and mechanisms for CD38 in macrophage activation and sepsis-induced acute kidney injury (AKI) remain to be determined. Here we report that in cultured macrophages, Lipopolysaccharide (LPS) could upregulate CD38 expression in time and dose dependent manner. Knocking down or blockade of CD38 in macrophages could inhibit LPS-induced macrophage M1 polarization accompanied by diminished NF-κB signaling activation. In mouse model with LPS-induced acute kidney injury, blocking CD38 with quercetin could significantly relieve kidney dysfunction, kidney pathological changes as well as inflammatory cell accumulation. Similar to those in the cultured cells, quercetin could inhibit macrophage M1 polarization and NF-κB signaling activation in macrophages from kidneys and spleens in mice after LPS injection. Together, these results demonstrate that CD38 mediates LPS-induced macrophage activation and AKI, which may be treated as a therapeutic target for sepsis-induced AKI in patients.

Keywords: AKI; CD38; Sepsis.

MeSH terms

ADP-ribosyl Cyclase 1 / antagonists & inhibitors
ADP-ribosyl Cyclase 1 / genetics*
ADP-ribosyl Cyclase 1 / immunology
Acute Kidney Injury / chemically induced
Acute Kidney Injury / drug therapy*
Acute Kidney Injury / genetics
Acute Kidney Injury / immunology
Animals
Antioxidants / pharmacology
Gene Expression Regulation
Kidney / drug effects
Kidney / immunology
Kidney / pathology
Lipopolysaccharides
Macrophage Activation / drug effects
Macrophages, Peritoneal / drug effects*
Macrophages, Peritoneal / immunology
Macrophages, Peritoneal / pathology
Male
Membrane Glycoproteins / antagonists & inhibitors
Membrane Glycoproteins / genetics*
Membrane Glycoproteins / immunology
Mice
Mice, Inbred C57BL
NF-kappa B / antagonists & inhibitors
NF-kappa B / genetics*
NF-kappa B / immunology
Primary Cell Culture
Quercetin / pharmacology
RAW 264.7 Cells
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Sepsis / chemically induced
Sepsis / drug therapy*
Sepsis / genetics
Sepsis / immunology
Signal Transduction
Spleen / drug effects
Spleen / immunology
Spleen / pathology

Substances

Antioxidants
Lipopolysaccharides
Membrane Glycoproteins
NF-kappa B
RNA, Small Interfering
Quercetin
Cd38 protein, mouse
ADP-ribosyl Cyclase 1