Pemt Deficiency Ameliorates Endoplasmic Reticulum Stress in Diabetic Nephropathy

Abstract

Phosphatidylethanolamine N-methyltransferase (Pemt) catalyzes the methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) mainly in the liver. Under an obese state, the upregulation of Pemt induces endoplasmic reticulum (ER) stress by increasing the PC/PE ratio in the liver. We targeted the Pemt gene in mice to explore the therapeutic impact of Pemt on the progression of diabetic nephropathy and diabetes, which was induced by the injection of streptozotocin (STZ). Although the blood glucose levels were similar in STZ-induced diabetic Pemt+/+ and Pemt−/−mice, the glomerular hypertrophy and albuminuria in Pemt−/− mice were significantly reduced. Pemt deficiency reduced the intraglomerular F4/80-positive macrophages, hydroethidine fluorescence, tubulointerstitial fibrosis and tubular atrophy. The expression of glucose-regulated protein-78 (GRP78) was enriched in the renal tubular cells in STZ-induced diabetic mice, and this was ameliorated by Pemt deficiency. In mProx24 renal proximal tubular cells, the treatment with ER-stress inducers, tunicamycin and thapsigargin, increased the expression of GRP78, which was reduced by transfection of a shRNA lentivirus for Pemt (shRNA-Pemt). The number of apoptotic cells in the renal tubules was significantly reduced in Pemt−/− diabetic mice, and shRNA-Pemt upregulated the phosphorylation of Akt and decreased the cleavage of caspase 3 and 7 in mProx24 cells. Taken together, these findings indicate that the inhibition of Pemt activity ameliorates the ER stress associated with diabetic nephropathy in a model of type 1 diabetes and corrects the functions of the three major pathways downstream of ER stress, i.e. oxidative stress, inflammation and apoptosis.

Hepatic PEMT activity mediates liver health, weight gain, and insulin resistance

“…Although PEMT is predominantly found in the liver, we have detected PEMT protein in other tissues, such as adipose and testis (2). Others have reported PEMT protein in kidneys; however, we could not reproduce this result using our in-house developed antibody (2,15). We hypothesized that the phenotype observed in HFD-fed Pemt 2/2 mice is dependent upon hepatic PEMT activity.…”

“…Our lab has previously shown that whole-body PEMTknockout mice are protected against DIO and IR (3). Because PEMT protein has been found in other tissues such as white adipose tissue and testis, we aimed to delineate the role of PEMT, specifically in the liver, in weight gain and IR (2,15). We restored hepatic PEMT in Pemt 2/2 mice by AAV-mediated expression.…”

Comprehensive Lipidome Profiling of the Kidney in Early-Stage Diabetic Nephropathy

“…The conversion of PE to PC is catalyzed by phosphatidylethanolamine N-methyltransferase (Pemt). Glomerular hypertrophy and albuminuria have been shown to be significantly attenuated in Pemt-deficient mice as a result of a decrease in the ratio of PC/PE and alleviation of ER stress (28). Interestingly, although most phospholipids declined, a specific side chain, 36:1, was increased in almost every phospholipid, including PE, PI, PA, PG PC, and PS.…”

Tubular atrophy in the pathogenesis of chronic kidney disease progression

“…Multiple apoptosis pathways have been implicated in tubular atrophy, including recent reports linking proximal tubule endoplasmic reticulum (ER) stress in diabetic nephropathy [29, 30]. Until recently the most compelling argument that apoptosis is the cause of tubular atrophy had been kinetic experiments demonstrating that proximal tubule apoptosis precedes tubular atrophy in mouse models of focal and segmental glomerulosclerosis (FSGS) [22].…”