Protective Effects Of Fosinopril On Rats With Diabetic Nephropathy

Objective:In recent years the number of people with diabetes has been undergoing rapid growth. Diabetic nephropathy, as one of the most important microvascular complications in diabetic patients, has drawn increasing attention since it can cause chronic kidney damage and eventually renal failure. Angiotensin converting enzyme inhibitors (ACEI) can decrease urinary proteins and delay the progression of diabetic nephropathy. Therefore, ACEI is widely used clinically in the treatment of diabetic nephropathy. However, the mechanisms of renal protection of ACEI are not very clear. To investigate the mechanisms of ACEI in the treatment of diabetic nephropathy, we studied the effects of fosinopril on blood biochemical parameters,24h urinary proteins, path-morphological changes in renal cortex, and the mass spectrometry of renal cortex.Methods:We used spontaneous type2diabetic and diabetic nephropathy (OLETF) rats and LETO rats with similar genetic background, age, and same gender. There are three groups:healthy control (LETO rats), diabetic nephropathy (OLETF rats), and OLETF rats treated with fosinopril. Blood glucose and24hour urinary proteins were measured once every four weeks. At week36and56, rats were slaughtered to measure blood biochemical parameters and semi-quantitatively assess the pathological changes in renal cortex and interstitial. Renal cortex was dissected and total proteins from cytoplasmic membrane and cytoplasm were isolated and used for two-dimensional gel electrophoresis (2-DE). The gel was stained with Coomassie Blue and the images were scanned and analyzed with ImageMaster software. After the differentially expressed protein spots were determined, the protein spots were cut and digested and analyzed with MALDI-TOF-MS-MS to obtain PMF. Protein identification of MS data was accomplished using matrixscience database and classified by GoMiner software.Results:Starting from6week old OLETF rats showed significantly higher blood glucose and24h urinary proteins compared to normal control rats and the differences became more obvious progressively. This shows that the diabetic nephropathy model is established. Treatment with fosinopril reduced24h urinary protein content and glomerulosclerotic index. Results from proteomics study shows that compared with OLETF diabetic rats without treatment, abundance of17proteins were significantly changed in kidney tissues from36and56week-old rats. Treated with fosinopril. GPX3and PDHB were upregulated, while DPYS12, PBLD, FAHD1and selenium binding protein2were downregulated at36week. HSPA9, AP0A1, GPX3, FBP1, ESD and MDH1were upregulated, while DPYS12, PGK1, ECHS1, PBLD, ETFA, FAHD1, NME2and selenium binding protein2were downregulated at56week. The proteins above-mentioned are involved in oxidative stress, apoptosis, and glucose and lipid metabolism.Conclusion:Fosinopril has strong protective effects on kidney. Fosinopril can significantly decrease urinary proteins and reduce glomerulosclerosis and interstitial fibrosis. We propose that fosinopril ameliorates renal injury through lessening oxidative stress, inhibiting apoptosis, and further improving glucose and lipid metabolism.