EIF2α/ATF4 pathway enhances proliferation of mesangial cell via cyclin D1 during endoplasmic reticulum stress in IgA nephropathy

IgA nephropathy (IgAN) is an essential cause of kidney failure and end-stage kidney disease worldwide. Mesangial hypercellularity is an important characteristic of IgAN, but the underlying mechanism remains unclear. Endoplasmic reticulum (ER) stress is a series of stress responses to restore the function of endoplasmic reticulum. We aimed to explore how ER stress functioned in kidneys of IgAN. We first examined ER stress in IgAN kidneys in vivo and in vitro, by testing the levels of ER stress associated proteins (BIP, p-eIF2α and ATF4). Our results showed that ER stress was activated in IgAN patients, mice and cell model. ER stress activation was related to the distribution of IgA deposition and the degree of mesangial proliferation. To determine the role of ER stress in mesangial cell (MC) proliferation of IgAN, we then tested the levels of ER stress and MC proliferation (cyclin D1, cell viability and cell cycle) through inhibiting ER stress associated proteins. After inhibiting ER stress associated proteins, ER stress was inactivated and cell proliferation was inhibited in MCs. We also explored the correlation between ER stress in the glomerulus and the clinical outcomes of IgAN patients in a prospective study. Patients with lower expression of p-eIF2α or ATF4 had higher rates of hematuria remission, proteinuria remission and clinical remission. In summary, our work outlines that in IgAN, ER stress mediated by eIF2α/ATF4 pathway promotes MC proliferation via up-regulating the expression of cyclin D1. Furthermore, p-eIF2α and ATF4 in the glomerulus negatively correlate with the clinical remission of IgAN patients.