GDC-0879 Microinflammation and subsequent extracellular matrix expansion are common pathways for the progression of diabetic nephropathy. In recent years, many researchers have demonstrated that the inflammation pathways play central roles in the progression of diabetic nephropathy, and the identification of the inflammatory molecules involved in this process may lead to the development of new therapeutic strategies. The molecules related to the inflammation pathways in diabetic nephropathy include transcription factors, proinflammatory cytokines, chemokines, adhesion molecules, Toll-like receptors, adipokines and nuclear receptors, which are candidate molecular targets for the treatment of diabetic nephropathy. The inhibition of Pemt and amelioration of ER stress is an emerging target for treating the microinflammation in diabetic nephropathy. During the process of ER stress, ROS, caspase-3, caspase-12, and mammalian target of rapamycin promote the induction of apoptosis. In contrast, the downregulation of Akt signaling and knock-out of CHOP in mice were demonstrated to facilitate the process of ER-induced apoptosis. In the case of diabetic nephropathy, long-term hyperglycemia downregulates the Akt activation and contributes to enhanced p38 mitogen-activated protein kinase activation and the apoptosis of renal tubular cells. In our study, we observed that Pemt deficiency relieved the ER stress, activated the phosphorylation of Akt and prominently reduced the apoptosis of proximal tubular cells. The relationship between Pemt and Akt signaling was already reported in hepatocytes, where the overexpression of Pemt downregulated the PI3K/Akt signaling. Taken together, the inhibition of Pemt activity appears to ameliorate the ER stress associated with diabetic nephropathy, and to correct the subsequent three major pathways downstream of ER stress, i.e. oxidative stress, inflammation and apoptosis. During the search for small molecules that upregulate GRP78 expression, GRP78 inducers such as trans-4,5-dihydroxy-1,2- dithiane and BiP inducer X were identified. In addition, extensive efforts were made to identify chemical chaperones. These studies demonstrated that 4-phenylbutyrate improves the ER folding capacity and facilitates the trafficking of unfolded proteins, and the endogenous bile acid derivatives, such as tauroursodeoxycholic acid, also protect cells against ER stress-induced apoptosis. The current study suggests that the identification of small molecules which inhibit the Pemt activity may be useful in the amelioration of ER stress and ER stress-induced apoptosis in diabetic nephropathy. In addition to our findings, Pemt inhibition has been previously reported to have therapeutic potential for insulin resistance and obesity, and also for the prevention of atherosclerosis. Therefore, Pemt inhibitors may be useful in the treatment of diabetic nephropathy in patients with type 1 diabetes, as well as for other ER stress- and oxidative stress-related diseases.