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The proliferation of glomerular mesangial cells (GMCs) and secretion of extracellular matrix (ECM) in rat Thy‐1 nephritis (Thy‐1N), resembling human mesangioproliferative glomerulonephritis (MsPGN), have been studied for many years, but the mechanisms, especially the role of signalling pathway activation and its regulation in GMCs triggered by sublytic C5b‐9 complexes in Thy‐1N rats remain largely unclear. In the study, the proliferation of GMCs and production of ECM as well as the role of PI3K/Akt and its regulation, both in GMCs induced by sublytic C5b‐9 (in vitro) and in the renal tissues of rats with Thy‐1N (in vivo), were determined and the results revealed that GMCs proliferation and ECM secretion, both in vitro and in vivo, were notably increased, and that PI3K/Akt1 activation and its regulation, such as TNF receptor‐associated factor 6 (TRAF6)‐mediated Akt1 ubiquitination and PI3K‐dependent Akt1 …