Knockdown of Cxcl10 Inhibits Mesangial Cell Proliferation in Murine Habu Nephritis Via ERK Signaling

Abstract

Background/Aims: IFN-γ-inducible protein 10 (IP-10, CXCL10) has been widely demonstrated to be involved in chemotaxis, cell growth regulation and angiogenesis inhibition. It has been reported that CXCL10 expression is significantly increased in patients with MesPGN (Mesangial proliferative glomerulonephritis). However, the underlying mechanism of CXCL10 in MesPGN reminds unclear. Methods: Wildtype (Cxcl10^+/+) mice and Cxcl10-deficient (Cxcl10^-/-) mice were used to generate a murine model of MesPGN. The histological changes in glomeruli were examined by PAS staining (Periodic Acid-Schiff staining), and cell proliferation was detected by PCNA immunohistochemistry staining. The expression of cell cycle regulatory proteins was analyzed by Western blotting and the effects of CXCL10 on primary mouse renal mesangial cells (MRMC) proliferation were detected using the EDU assay. Furthermore, the specific mechanisms by which CXCL10 affected mesangial cells were investigated in vitro using a specific inhibitor. Results: Typical pathological phenotypes were observed in both mouse types, while the Cxcl10^-/- mice had lighter accumulation of extracellular matrix, less cell proliferation and diminished up-regulation of cell cycle regulatory proteins compared to Cxcl10^+/+ mice at day 7. Furthermore, we observed that CXCL10 inhibition resulted in less activation of ERK phosphorylation, and ERK pathway inhibition by a specific inhibitor, U0126, prevented CXCL10 induced MRMC proliferation and the activation of phosphorylated ERK. Conclusions: CXCL10 may aggravate mesangial proliferation in MesPGN by activating the ERK signaling pathway. These results provide a novel insight into the mechanism and potential therapy target of MesPGN.

Role of Chemokine (C–X–C Motif) Ligand 10 (CXCL10) in Renal Diseases

“…To further investigate the proliferation effect of CXCL10 in MesPGN, our previous study used Cxcl10-deficient mice (Cxcl10 -/mice) to generate a Habu nephritis model, a classical experimental model that develops glomerular lesions similar to those of human MesPGN, and found that Cxcl10 -/mice exhibited mitigated proliferation with less extracellular matrix accumulation and fewer cells in the glomeruli compared with wild-type mice in the mesangial proliferation period, which peaked on day 7 after HSV injection. In addition, we hypothesized that CXCL10 modulates cell cycle regulatory proteins to promote mesangial proliferation via the ERK signaling pathway, as confirmed in vitro using primary mouse mesangial cells [55]. Our data, together with those reported previously by Romagnani et al, were consistent with a cell type-specific proliferative effect of CXCL10 and suggested the potential therapeutic target of CXCL10 on cell proliferation.…”

Age‐related decline of interferon‐gamma responses in macrophage impairs satellite cell proliferation and regeneration

“…43 Recently, a series of studies showed that CXCL10 also could play roles in regulating cell proliferation, apoptosis, differentiation, and angiogenesis. [24][25][26][27] Our finding that expression of CXCL10 was accompanied by an increase of IFN-γ at the late stage after injury, while the inflammatory cells were recruited from circulation mainly at the early stage after injury, hints a novel role of CXCL10 in skeletal muscle repair. We found that MuSCs also expressed the receptor of CXCL10 and CXCR3.…”

“…Despite its chemotactic nature, CXCL10 is also reported to be a cytokine associated with cell proliferation, apoptosis, differentiation, and angiogenesis. [24][25][26][27] The receptor of CXCL10 is CXCR3, a G protein-coupled receptor expressed mainly in immune cells and other somatic cells. In uninjured young muscle, CXCR3 was expressed mostly in CD45 À CD31 À α7integrin + MuSCs (75.7%) as assessed by flow cytometry.…”

Paeoniflorin Inhibits Mesangial Cell Proliferation and Inflammatory Response in Rats With Mesangial Proliferative Glomerulonephritis Through PI3K/AKT/GSK-3β Pathway

“…The activated and proliferative mesangial cells in the glomerulus could produce kinds of vasoactive substances and cytokines including interleukin-1 (IL-1), interferon (IFN) and chemotactic factor (CXC), thereby promoting ongoing mesangial cell proliferation (Gao et al, 2017). In fact, inflammation plays a key role in the development of MPGN, including anti-Thy1 nephritis and IgA nephropathy animal models (Hua et al, 2013; Aizawa et al, 2014).…”