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

Background/Aims: IFN-gamma-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. (C) 2017 The Author(s) Published by S. Karger AG, Basel