Prevention of lipopolysaccharide-induced CD11b+ immune cell infiltration in the kidney: role of AT2 receptors.

Sanket Patel,Isha Dhande,Quaisar Ali,Tahir Hussain,Elizabeth Alana Gray

doi:10.1042/bsr20190429

Sanket Patel, Isha Dhande + Show 3 more

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https://doi.org/10.1042/bsr20190429

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Journal: Bioscience reports	Publication Date: May 24, 2019
Citations: 16	License type: CC BY 4.0

Affiliation: University of Houston

Abstract

Immune cell infiltration plays a central role in mediating endotoxemic acute kidney injury (AKI). Recently, we have reported the anti-inflammatory and reno-protective role of angiotensin-II type-2 receptor (AT2R) activation under chronic low-grade inflammatory condition in the obese Zucker rat model. However, the role of AT2R activation in preventing lipopolysaccharide (LPS)-induced early infiltration of immune cells, inflammation and AKI is not known. Mice were treated with AT2R agonist C21 (0.3 mg/kg), with and without AT2R antagonist PD123319 (5 mg/kg) prior to or concurrently with LPS (5 mg/kg) challenge. Prior-treatment with C21, but not concurrent treatment, significantly prevented the LPS-induced renal infiltration of CD11b+ immune cells, increase in the levels of circulating and/or renal chemotactic cytokines, particularly interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) and markers of renal dysfunction (blood urea nitrogen and albuminuria), while preserving anti-inflammatory interleukin-10 (IL-10) production. Moreover, C21 treatment in the absence of LPS increased renal and circulating IL-10 levels. To investigate the role of IL-10 in a cross-talk between epithelial cells and monocytes, we performed in vitro conditioned media (CM) studies in human kidney proximal tubular epithelial (HK-2) cells and macrophages (differentiated human monocytes, THP-1 cells). These studies revealed that the conditioned-media derived from the C21-treated HK-2 cells reduced LPS-induced THP-1 tumor necrosis factor-α (TNF-α) production via IL-10 originating from HK-2 cells. Our findings suggest that prior activation of AT2R is prophylactic in preventing LPS-induced renal immune cell infiltration and dysfunction, possibly via IL-10 pathway.

Highlights

Acute kidney injury (AKI) is associated with significant morbidity and mortality in critically ill patients and in those who have undergone major surgery (30–60%) [1]
Thick free-floating kidney sections were stained for CD11b+ (Figure 1A) and increase in number of CD11b+ cells was considered as an index of immune cell infiltration (Figure 1B, all values are reported in number of cells per high power field (HPF))
We attempted to identify the involvement of the angiotensin-II type-2 receptor (AT2R) in preventing renal accumulation of CD11b+ immune cells that mainly include monocytes, neutrophils and natural killer cells, potential LPS-driven mediators of renal inflammation and injury

Summary

Introduction

Acute kidney injury (AKI) is associated with significant morbidity and mortality in critically ill patients and in those who have undergone major surgery (30–60%) [1]. Multiple reports suggest that rolling and infiltration of circulating immune cells, of leukocytes (monocytes and neutrophils) and natural killer T lymphocytes, is a key initiating event in the pathogenesis of AKI [2]. The homing of these cells is heterogeneous and believed to be regulated in response to local release of cytokines such as monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) or interleukin-10 (IL-10) by both immune cells and injured renal cells. It has been reported that depletion of mononuclear phagocytes, including monocytes, before the occurrence of kidney injury attenuated the rise in BUN and provided renoprotection [3]

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