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

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.

Analysis of long noncoding RNAs and messenger RNAs expression profiles in the hearts of mice with acute viral myocarditis

“…41 As an important chemokine for the recruitment of macrophages, Ccl9 was reported to be involved in various types of inflammatory diseases, such as atherosclerosis, 42 enteritis, 43 and chronic kidney disease. 44 Increased Ccl9 expression has also been observed in rat models of left-ventricular hypertrophy. 45 Here, a total of 9 upregulated lncRNAs were positively correlated with Ccl9, indicating that these lncRNAs may participate in the molecular mechanism of AVMC by mediating Ccl9 action.…”

“…Among them, Ccl9 (also called MIP‐1γ), a member of the macrophage inflammatory protein (MIP)‐1 CC chemokine subfamily, was significantly overexpressed in AVMC and regulated by most DElncRNAs 41 . As an important chemokine for the recruitment of macrophages, Ccl9 was reported to be involved in various types of inflammatory diseases, such as atherosclerosis, 42 enteritis, 43 and chronic kidney disease 44 . Increased Ccl9 expression has also been observed in rat models of left‐ventricular hypertrophy 45 .…”

Mitochondrial Impairment: A Link for Inflammatory Responses Activation in the Cardiorenal Syndrome Type 4

“…TLRs, NLRP3, and cGAS-STING pathways produce the upregulation of cytokines, vasoactive substances, chemokines, and inflammatory responses [46][47][48]. Chemokine's overstimulation produces the recruitment of leukocytes to tissues and dysregulated infiltration, leading to chronic cardiac damage [49][50][51]. Interestingly, experimental studies have shown that chemokines are upregulated in the heart during CKD, establishing a link for CRS type 4 development [52,53].…”