Chemokine CCL9 Is Upregulated Early in Chronic Kidney Disease and Counteracts Kidney Inflammation and Fibrosis.

Christian Hemmers,Joachim Jankowski,Thimoteus Speer,Julia Wollenhaupt,Dickson W L Wong,Michael Böhm,Corinna Schulte,Heidi Noels,Barbara Mara Klinkhammer,Setareh Orth-Alampour,Nikolaus Marx,Stephan H Schirmer,Eva Harlacher,Peter Boor

doi:10.3390/biomedicines10020420

Christian Hemmers, Joachim Jankowski + Show 12 more

Open Access

https://doi.org/10.3390/biomedicines10020420

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Abstract

Inflammation and fibrosis play an important pathophysiological role in chronic kidney disease (CKD), with pro-inflammatory mediators and leukocytes promoting organ damage with subsequent fibrosis. Since chemokines are the main regulators of leukocyte chemotaxis and tissue inflammation, we performed systemic chemokine profiling in early CKD in mice. This revealed (C-C motif) ligands 6 and 9 (CCL6 and CCL9) as the most upregulated chemokines, with significantly higher levels of both chemokines in blood (CCL6: 3–4 fold; CCL9: 3–5 fold) as well as kidney as confirmed by Enzyme-linked Immunosorbent Assay (ELISA) in two additional CKD models. Chemokine treatment in a mouse model of early adenine-induced CKD almost completely abolished the CKD-induced infiltration of macrophages and myeloid cells in the kidney without impact on circulating leukocyte numbers. The other way around, especially CCL9-blockade aggravated monocyte and macrophage accumulation in kidney during CKD development, without impact on the ratio of M1-to-M2 macrophages. In parallel, CCL9-blockade raised serum creatinine and urea levels as readouts of kidney dysfunction. It also exacerbated CKD-induced expression of collagen (3.2-fold) and the pro-inflammatory chemokines CCL2 (1.8-fold) and CCL3 (2.1-fold) in kidney. Altogether, this study reveals for the first time that chemokines CCL6 and CCL9 are upregulated early in experimental CKD, with CCL9-blockade during CKD initiation enhancing kidney inflammation and fibrosis.

Highlights

Chronic kidney disease (CKD), with an estimated global prevalence of more than10% [1], is defined by a decrease in kidney filtration function and/or the presence of kidney damage markers for over 90 days [2]
Chemokines CCL6 and CCL9 Are Increased in chronic kidney disease (CKD)
This revealed a significant increase in CCL6, with CCL9 being the chemokine with the second highest upregulation (Figure 1a)

Summary

Introduction

Chronic kidney disease (CKD), with an estimated global prevalence of more than10% [1], is defined by a decrease in kidney filtration function and/or the presence of kidney damage markers for over 90 days [2]. In addition to CKD burden, patients with CKD suffer from increased risk of cardiovascular disease, with CKD identified as an independent risk factor of cardiovascular morbidity and mortality [3,4]. In both diseases, organ inflammation and fibrosis play important pathophysiological roles. Initial kidney injury triggers the expression of pro-inflammatory mediators as well as the recruitment and accumulation of inflammatory leukocytes, including neutrophils, monocytes and macrophages, in the kidney. These contribute to further organ damage and produce pro-fibrotic mediators triggering fibrotic phenotypes [5–7]. Patients with CKD often exhibit kidney fibrosis, detectable as glomerulosclerosis, arterio- and arteriolosclerosis and/or tubulointerstitial fibrosis, which is associated with an impairment of kidney function [8,9]

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