Fatty Acid Synthase Promotes Podocyte and Mesangial Cell Injury in Lupus Nephritis

Background: High proportion of Lupus nephritis (LN) patients progress to end stage kidney disease due to the insufficient understanding of its mechanisms. Recent study reports that reducing renal lipid accumulation can ameliorate several kidney diseases. We aim to clarify whether fatty acid synthase (FASN) promotes podocyte and mesangial cell injury in lupus nephritis through reducing lipid accumulation in kidneys. Methods: FASN expression in LN patients' kidneys predicted by bioinformatic analysis. Renal tissue of LN patients and Fcgr2b-/- spontaneous LN mice were applied for in vivo study. Mesangial cells and podocytes were used for in vitro study including overexpression or knockdown of FASN. Oil Red O staining on kidney sections from LN patients and LN model mice was used to examine renal lipid accumulation in vivo. BODIPY lipid fluorescence staining to analyze intracellular lipid accumulation in vitro. PAS and Masson's trichrome staining were employed to assess glomerular injury and fibrosis. Western blotting and immunofluorescence staining were conducted to examine the expression of FASN, mesangial cell marker ITGA8, podocyte injury markers (WT-1 and podocin), as well as fibrosis markers (FN and COL1). Results: FASN increased in mesangial cells and podocytes of glomeruli of LN patients, meanwhile Oil Red O positive lipid droplet accumulation was seen in glomeruli. In Fcgr2b-/- spontaneous LN, mesangial cells increased and podocyte vacuolar changes and detachment showed on PAS staining, and glomerulosclerosis was seen on Masson's trichrome staining. FASN increased in LN mice glomeuli on Western Blotting and immunofluorescent staining. Oil Red O positive staining was also seen in LN mouse glomeruli. At same time, WT-1 and podocin decreased, ITGA8 increased, and FN and COL1 increased. In mesangial cells and podocytes with hTGF-β stimulation, similar results were seen as in vivo. In addition, overexpression of FASN in both mesangial cells and podocytes, FASN, lipid accumulation, and cell type specific molecules and profibrotic molecules showed same change direction as LN glomerular cells as well as BODIPY lipid fluorescence staining extend. Meanwhile, these molecular changes induced by hTGF-βwere reversed by FASN knockdown using siRNA. Conclusion: FASN may cause mesangial cells proliferation and podocytes injury in LN kidney by promoting lipid synthesis and accumulation. Funding: Government Support – Non-U.S.