| The Diverse Effects of Different Dosages of Pioglitazone on the Renal Dysfunctions in Uninephrectomized Diabetic RatsBackground. Thiazolidinedione (TZD) compounds are widely used as oral hypoglycemic agents. Until now, three TZDs, troglitazone, pioglitazone and rosiglitazone, have been used in clinical trials and animal experiments. Several recent studies have suggested a renoprotective function of this kind of drugs under some disease conditions, such as diabetes, hypertension, subtotal nephrectomy and mesangial proliferative glomerulonephritis, etc. However, till now, as to the available literature, there is few study of systematic observation and investigation about the effects of TZDs on the diabetic nephropathy. So, in this study we undertook to observe the effects of different dosages of pioglitazone, a kind of TZDs, on the Uninephrectomized diabetic rats.Methods. Uninephrectomized male Wistar rats (180-200g) were randomly assigned to five groups: non-diabetic control rats (CTR), diabetic rats without treatment (DM), 3mg/kg-d pioglitazone treated diabetic rats (DM-LP), 9mg/kg-d pioglitazone treated diabetic rats (DM-MP) and diabetic rats treated with 20mg/kg-d pioglitazone (DM-HP). After 10 weeks of drug gavage, systolic blood pressure was examined and 24 hour urine was collected before the rats were sacrificed, then blood sample and left kidney were harvested. Blood glucose, serum triglyceride (TG), serum total cholesterol (TC), serum insulin level, 24-hour urinary protein excretion and kidney hypertrophy index (LK/BW) were examined. Periodic acid-schiff (PAS) stain was used to measure the glomerular extracelluar matrix (ECM) deposition. Results. Compared with CTR, DM demonstrated hyperglycemia, hyperlipidemia,hypertension and significantly increased urinary protein excretion and LK/BW. Contrasted to DM, DM-LP showed no changes in blood glucose, serum TG and CHO and SBP, but the proteinuria and glomerular ECM deposition were ameliorated significantly; Still compared with DM, DM-MP had greatly attenuated BG and serum TG, but not SBP and TC, its proteinuria and ECM deposition are similar to DM-LP; Besides the comparable control of BG and serum TG, DM-HP showed a detectable decline of SBP compared with DM-MP, meanwhile, there is a further attenuation of proteinuria and pathological progress in this group. Conclusions. The results of this part of study suggested that different dosages of pioglitazone might have diverse effects on the uninephrectomized diabetic rats. The dosage of 3mg/kg-d pioglitazone have beneficial effects which are independent of its metabolic effects. Although 9mg/kg-d pioglitazone might ameliorate the metabolic disorders in diabetic rats, it failed to show further benign effects on the renal pathological progress compared with the dosage of 3mg/kg-d. Furthermore, 20mg/kg-d pioglitazone could ameliorate the hypertension of uninephrectomized diabetic rats, at the same time, its effects of decreasing proteinuria and delaying renal pathological progress were strengthened further.PART IINon-Metabolic Effects of Pioglitazone on Proteinuria and RenalFibrosis in Uninephrectomized Diabetic Ratsand Involved MechanismsBackground. Thiazolidinedione compounds (TZDs) are widely used as oral hypoglycemic agents. Several recent studies have suggested the renoprotection function of this kind of drugs. It is generally believed that TZDs exert insulin-sensitizing activity through activation of peroxisome proliferator-actived receptor (PPAR)7, a transcriptional factor of nuclear receptor family. We addressed this study to explore whether pioglitazone, a TZD, affects the proteinuria and renal fibrosis of uninephrectomized diabetic rats and the possible mechanisms involved. Methods. Uninephrectomized male Wistar rats (180-200g) were randomly assigned to four groups: non-diabetic control rats (CTR), non-diabetic rats treated with 3mg/(kg-d) pioglitazone (CTR-LP), low dose (35mg/kg) streptozotocin-induced diabetic rats (DM), and 3mg/(kg-d) pioglitazone-treated diabetic rats(DM-LP).
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