α-Ketoglutarate was recently identified as the endogenous ligand of GPR80, a member of orphan G protein-coupled receptors (oGPCR). However, the physiological and pathological meanings of α-ketoglutarate receptor still remain unclear. Because kidney is the tissue where α-ketoglutarate receptor mRNA was highly expressed, we have conducted in vivo and in vitro experiments to explore its correlation with diabetic nephropathy (DN). A model of rats with DN were induced by once intraperitoneal injection of streptozotocin (STZ) at a dose of 65mg/Kg, and α-ketoglutarate receptor protein expression was examined with immunohistochemical method at 6, 10, 12, 16 and 32 weeks after STZ injection. It was found that the protein expression of α-ketoglutarate receptor in the medullary loop of the DN rat kidney was increased from 6 weeks on. To mimic the situation of DN, the cultured rat renal tubular epithelial cells(RTEC)were exposed to a high concentration of glucose (30mmol/L). By using MTT colorimetric method and RT-PCR, effects of the high concentration of glucose with or without α-ketoglutarate sodium on the RTEC proliferation and TGF-β,α-SMA and MCP-1 mRNA expressions were detected. It was indicated that high concentration of glucose-treated RTEC was higher in its proliferation and TGF-β,α-SMA and MCP-1 mRNA expressions, but α-ketoglutarate sodium could inhibit the above effects of glucose. In conclusion, relevance between α-ketoglutarate receptor and DN implied that α-ketoglutarate receptor might be involved in the development of DN. Key words: α-Ketoglutarate receptor; GPR80; Diabetic nephropathy; Rat