Activation of Cyclooxygenase-2 by ATF4 During Endoplasmic Reticulum Stress Regulates Kidney Podocyte Autophagy Induced by Lupus Nephritis

Cellular Physiology and Biochemistry

Juan Jin¹ 

关键词: Lupus Nephritis;    Autophagy;    Endoplasmic reticulum stress;    COX-2;    ATF4;   

DOI  :  10.1159/000491904

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Background/Aims Autophagy plays an essential role in lupus nephritis (LN)-induced kidney injury, although the mechanism of action remains obscure. We investigated the role of cyclooxygenase-2 (COX-2) and the ATF4 endoplasmic reticulum (ER) stress pathway in LN-induced podocyte autophagy. Methods We evaluated podocyte autophagy in a mouse model of LN. Protein levels of COX-2 and ATF4, and markers of autophagy, were evaluated by immunofluorescence and western blotting. To evaluate apoptosis, levels of PGE2 were measured by enzyme-linked immunosorbent assay. Results LN induced kidney damage and dysfunction, which was associated with podocyte autophagy. COX-2 and the ATF4 ER stress pathway were induced by LN in cultured podocytes. Inhibition of COX-2 inhibited LN-induced autophagy in podocytes. In addition, blocking ER stress with 4-phenylbutyrate or RNAi partially counteracted COX-2 overexpression and LN-induced autophagy, suggesting that ER stress is required for LN-induced kidney autophagy. Furthermore, LN activated ATF4 and induced its nuclear translocation. Knockdown of ATF4 inhibited LN-induced COX-2 overexpression. Conclusions Our study suggests a novel molecular mechanism by which COX2 overexpression, induced by the ATF4 ER stress pathway, contributes to LN-induced kidney autophagy and injury. These data demonstrate that COX-2 may be a potential therapeutic target against LN-induced nephropathy.

【 授权许可】

CC BY-NC-ND