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

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

Zell-basierte Ansätze zur Therapie der renalen Fibrose

Almost all progressive renal diseases lead to chronic kidney disease (CKD) and development of renal fibrosis. With a prevalence of more than 10% worldwide new therapeutic options are urgently needed. Today's only option for patients with end stage renal disease (ESRD) is renal replacement therapy (dialysis and kidney transplantation). Mesenchymal stem cell (MSC) transplantation could represent such a new therapy since it has the potential for organ repair. Nevertheless, some factors might lessen the regenerative potential of MSCs, e.g. donor age or systemic disease. In addition, first reports showed both antifibrotic as well as profibrotic effects after MSC therapy in different organs. In the present study the effect of bone marrow MSC transplantation into rats with 5/6 nephrectomy (remnant kidney RK) was investigated. Repeated MSC applications failed to improve renal function or kidney fibrosis. Next we analyzed the effects of CKD on bone marrow MSC function. Bone marrow MSCs were isolated from CKD rats (remnant kidney (CKD-RK-MSC) and adenine induced nephropathy (CKD-AD-MSC)) and compared to healthy MSC. We found signs of premature senescence in vitro: reduced proliferation capacity, spontaneous adipogenesis and accummulation of actin stress fibers and senescence-associated-beta-galactosidase. The in vivo functionality of CKD-MSCs was tested in rats with acute anti-Thy1.1-nephritis, where healthy MSCs have been shown to be beneficial. Rats received healthy MSCs, CKD-RK-MSC, CKD-AD-MSC or medium by injection into the left renal artery. Kidneys receiving healthy MSCs exhibited accelerated healing of glomerular lesions, whereas CKD-RK-MSC or CKD-AD-MSC or medium exerted no benefit. Another histological analysis showed that CKD can also influence a newly identified intrarenal cell population, which might have progenitor qualities. Taken together this study shows that CKD can influence the phenotype and function of bone marrow MSC and intrarenal cells. CKD-MSC show signs of premature senescence which might account for a reduced regenerative capacity. This emphasizes the importance of further studies identifying uremia-associated mechanisms that account for altered MSC function to ensure clinical safety of autologous MSC therapy in human renal diseases