| IntroductionDiabetes mellitus is a group of metabolic diseases characterized by hyperglycemia. International Diabetes Federation expects that 592 million people worldwide will have diabetes by 2035, and 10% of diabetic patients will develop diabetic nephropathy (DN). DN is a common complication of diabetes with high mortality rates. In developed countries, DN is a leading cause of end-stage renal disease (ESRD), accounting for about 30% -40% of ESRD. In China, it accounts for approximately 16.4% of ESRD cases. Because of its complex metabolic disorder, atypical initial symptoms are rarely noticed.Diabetic nephropathy is characterized by excessive deposition of extracellular matrix (ECM). At advanced stage, thickening of glomerular basement membrane (GBM), mesangial expansion and nodular glomerulosclerosis (Kimmelstiel-Wilson lesions) can be observed. While it is widely accepted that the matrix-producing myofibroblasts in the renal interstitium are the major source of the increased ECM, their exact origin and activation process in renal interstitial fibrosis remains largely undefined and controversial. Recent studies suggest that activated myofibroblasts could derive from bone marrow cells, resident fibroblasts, endothelial cells, and tubular epithelial cells.Previous studies demonstrated that EMT was involved in renal interstitial fibrosis. However, differences in species and diabetes duration may have an important effect on the changes of diabetic nephropathy. Thus,non-human primate models, which have a close phylogenetic and immunological relationship with humans, are urgently needed to determine whether EMT is involved in renal interstitial fibrosis in diabetic nephropathy.AimsThis study aims to investigate the early events in diabetic nephropathy and the occurrence of EMT in interstitial fibrosis.Materials and MethodsEight male cynomolgus monkeys (2.5 to 4 years old) were induced into Type 1 diabetes mellitus by treatment with 68 mg/kg BW streptozocin(STZ). Then, blood glucose levels were monitored, and an intravenous glucose tolerance test (IVGTT) was performed after the STZ injection for evaluating stability and reliability of the model. Those diabetic monkeys were objectively divided into two groups: 1 year group and 4 years group, according to the final duration of diabetes. Age and sex-matched normal cynomolgus served as the control group. The following parameters were evaluated: (1) blood biochemistry and routine urinalysis, (2) H&E and masson staining, (3) electron photomicrographs, (4) immunostaining assay of EMT related markers:E-cadherin, ?-SMA, FSP1 and TGF- ?1.Results1. Serum and urinary biochemical test results revealed no obvious change in serum LDL, BUN, urinary ?2-MG and ACR at the different durations of diabetes, and total cholesterol concentrations significantly increased in diabetic monkeys(P <0.01).2. H&E and Masson-stained tissue sections revealed tubulointerstitial injury and glomerular damage in diabetic monkeys. The kidney in diabetic monkeys exhibited increased glomerular volume, tubular atrophy and renal interstitial fibrosis.3. Electron photomicrographs and stereological quantitative analysis showed that glomerular basement membrane, mesangial volume and PGBM surface per glomerulus were markedly increased in the 4 years group (P<0.05).4. Immunohistochemistrical results showed that diabetic cynomolgus monkeys showed no significant change in the expression of TGF-?1 and a -SMA compared with normal cynomolgus monkeys(P> 0.05).However, the expression of E-cadherin and FSP1 was significantly increased in renal sections in the diabetic monkeys (P <0.05). |
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