Sublytic C5b-9 triggers glomerular mesangial cell proliferation via enhancing FGF1 and PDGFα gene transcription mediated by GCN5-dependent SOX9 acetylation in rat Thy-1 nephritis

Rat Thy-1 nephritis (Thy-1N) is an animal model of human mesangioproliferative glomerulonephritis (MsPGN), accompanied by glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) deposition. Although sublytic C5b-9 formed on GMC membrane could induce cell proliferation, the mechanism is still unclear. In this study, we first demonstrated that the level of SRY related HMG-BOX gene 9 (SOX9), general control nonderepressible 5 (GCN5), fibroblast growth factor 1 (FGF1) and platelet-derived growth factor alpha (PDGF alpha) was all elevated both in the renal tissues of Thy-1N rats (in vivo) and in the GMCs (in vitro) with sublytic C5b-9 stimulation. Then, we not only discovered that sublytic C5b-9 caused GMC proliferation through increasing SOX9, GCN5, FGF1 and PDGF alpha expression, but also proved that SOX9 and GCN5 formed a complex and combined with FGF1 and PDGF alpha promoters, leading to FGF1 and PDGF alpha gene transcription. More importantly, GCN5 could mediate SOX9 acetylation at lysine 62 (K62) to enhance SOX9 binding to FGF1 or PDGF alpha promoter and promote FGF1 or PDGF alpha synthesis and GMC proliferation. Besides, the experiments in vivo also showed that FGF1 and PDGF alpha expression, GMC proliferation and urinary protein secretion in Thy-1N rats were greatly reduced by silencing renal SOX9, GCN5, FGF1 or PDGF alpha gene. Furthermore, the renal tissues of MsPGN patients also exhibited positive expression of these genes mentioned above. Collectively, our findings indicate that GCN5, SOX9 and FGF1/PDGF alpha can form an axis and play an essential role in sublytic C5b-9-triggered GMC proliferation, which might provide a novel insight into the pathogenesis of Thy-1N and MsPGN.

Automated summary

In this study, elevated levels of SOX9, GCN5, FGF1, and PDGF alpha were observed in the renal tissues of Thy-1N rats and GMCs stimulated with sublytic C5b-9. It was found that sublytic C5b-9 induced GMC proliferation by increasing the expression of SOX9, GCN5, FGF1, and PDGF alpha, and GCN5 mediated SOX9 acetylation to enhance FGF1 or PDGF alpha synthesis and GMC proliferation. Silencing renal SOX9, GCN5, FGF1, or PDGF alpha genes significantly reduced FGF1 and PDGF alpha expression, GMC proliferation, and urinary protein secretion in Thy-1N rats. Additionally, positive expression of these genes was also observed in the renal tissues of MsPGN patients.