Angiotensin II type 1 receptor expression is increased via 12-lipoxygenase in high glucose-stimulated glomerular cells and type 2 diabetic glomeruli.

BACKGROUND: Angiotensin II type 1 receptor (AT1) plays an important role in the development of diabetic nephropathy (DN). However, the roles played by 12-lipoxygenase (12-LO) in the AT1 expression in glomerular cells exposed to high glucose (HG) and diabetic glomeruli remain unclear. Our objective in the present study was to investigate the role of 12-LO in the AT1 expression in glomerular cells and glomeruli under diabetic conditions.
METHODS: Mesangial cells (MCs), podocytes and glomeruli isolated from rats were used in this study. The rats fed a high fat diet received low-dose streptozotocin to make type 2 diabetes. The 12-LO product 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] was infused to rats by osmotic mini-pump. Morphometric measurement for glomerular volume, competitive reverse transcription polymerase chain reaction for mRNA expression, western blot and immunohistochemistry for protein expression were performed, respectively.
RESULTS: Both the 12(S)-HETE and HG increased AT1 protein expression in MCs and podocytes. Furthermore, the levels of the AT1 were significantly higher in glomeruli derived from 12(S)-HETE-treated rats compared with control rats. In addition, HG-induced AT1 expression was significantly reduced by the 12-LO inhibitor cinnamyl-3,4-dihydroxy-alpha-cynanocinnamate (CDC). Compared with the non-diabetic controls, DN rats showed significant glomerular hypertrophy and albuminuria. This was associated with significant increases in AT1 protein expression. These abnormalities were prevented by treatment of the CDC.
CONCLUSIONS: These results indicate that AT1 expression is enhanced, at least in part, by 12-LO in the type 2 diabetic glomeruli, and 12-LO inhibition can ameliorate DN progression through downregulation of AT1 expression.