Trimetazidine has protective effects on spermatogenesis in a streptozotocin‐induced diabetic rat model

The aim of this study was to investigate the protective effects of trimetazidine (TMZ), as an antioxidant agent, on streptozotocin (STZ)‐induced diabetic rats. A total of 50 male Sprague Dawley rats were randomly classified into five groups as follows: Group 1 (control), Group 2 (STZ‐induced diabetic rats), Group 3 (STZ‐induced diabetic rats treated orally with 1 cc/day isotonic saline), Group 4 (diabetic rats treated orally with 10 mg/kg/day TMZ) and Group 5 (diabetic rats treated orally with 20 mg/kg/day TMZ). After 8 weeks, orchiectomy was carried out. Histopathological and electron microscopic examinations were performed in all groups. In groups 1 and 5, the structural and ultra‐structural findings of the testicular tissue and spermatogenesis were found normal. In groups 2, 3 and 4, similar results were obtained in terms of the impaired testicular architecture and degeneration of spermatogenesis. The administration of an optimal dose of TMZ protects against the harmful effects of diabetes mellitus on spermatogenesis in rats. TMZ therapy can be used to maintain normal spermatogenesis in diabetic rats.     

Polyphenolic Extract of Ichnocarpus Frutescens Attenuates Diabetic Complications in Streptozotocin-Treated Diabetic Rats

Diabetic nephropathy is one of the major complications of diabetes. Oxidative stress is implicated as an important mechanism by which diabetes causes nephropathy. The aim of the study was to examine the involvement of oxidative stress in the progression of nephropathy in STZ diabetic animals and to evaluate the potential of polyphenolic extract (PPE) in the treatment of diabetes mellitus. In this study, we examined whether prolonged oral administration of polyphenolic extract of Ichnocarpus frutescens could prevent the progress or improve the outcome of diabetic nephropathy induced by oxidative stress in STZ diabetic rats. Intraperitoneal glucose tolerance test (IPGTT) revealed a significant decrease in blood glucose levels at 180 min after glucose loading in Wistar albino rats fed with PPE. During the eight weeks of experimental period, diabetic rats exhibited wide range of symptoms, including loss of body weight, hyperglycemia, polyuria, proteinuria, renal enlargement, and total renal dysfunction. A significant increase in TBARS level was observed in diabetic kidney, which was accompanied by a significant decrease in enzymatic and non-enzymatic antioxidant levels. After eight weeks, PPE-treated groups showed a lower level of blood glucose compared with non-treated STZ diabetic rats. The increases in urinary albumin and protein after eight weeks of treatment were significantly inhibited by prolonged treatment with PPE. In addition, PPE attenuates the adverse effects on hepatic biomarkers. We found that PPE can effectively protect against aldose reductase activity and protein damage (albumin glycation), and showed that its action was mainly due to enriched polyphenolic content. Our results also showed that treatment with PPE normalized the increase in hyperalgesia (i.e., the response to thermal stimuli) associated with the induction of diabetes by STZ. PPE administration in diabetic rats clearly ameliorated diabetic complications, suggesting not only a natural antioxidant but also supportive therapy for the treatment of type II diabetes.     

Polyphenolic extract of Ichnocarpus frutescens attenuates diabetic complications in streptozotocin-treated diabetic rats

Diabetic nephropathy is one of the major complications of diabetes. Oxidative stress is implicated as an important mechanism by which diabetes causes nephropathy. The aim of the study was to examine the involvement of oxidative stress in the progression of nephropathy in STZ diabetic animals and to evaluate the potential of polyphenolic extract (PPE) in the treatment of diabetes mellitus. In this study, we examined whether prolonged oral administration of polyphenolic extract of Ichnocarpus frutescens could prevent the progress or improve the outcome of diabetic nephropathy induced by oxidative stress in STZ diabetic rats. Intraperitoneal glucose tolerance test (IPGTT) revealed a significant decrease in blood glucose levels at 180 min after glucose loading in Wistar albino rats fed with PPE. During the eight weeks of experimental period, diabetic rats exhibited wide range of symptoms, including loss of body weight, hyperglycemia, polyuria, proteinuria, renal enlargement, and total renal dysfunction. A significant increase in TBARS level was observed in diabetic kidney, which was accompanied by a significant decrease in enzymatic and non-enzymatic antioxidant levels. After eight weeks, PPE-treated groups showed a lower level of blood glucose compared with non-treated STZ diabetic rats. The increases in urinary albumin and protein after eight weeks of treatment were significantly inhibited by prolonged treatment with PPE. In addition, PPE attenuates the adverse effects on hepatic biomarkers. We found that PPE can effectively protect against aldose reductase activity and protein damage (albumin glycation), and showed that its action was mainly due to enriched polyphenolic content. Our results also showed that treatment with PPE normalized the increase in hyperalgesia (i.e., the response to thermal stimuli) associated with the induction of diabetes by STZ. PPE administration in diabetic rats clearly ameliorated diabetic complications, suggesting not only a natural antioxidant but also supportive therapy for the treatment of type II diabetes.     

Effect of angiotensin II on glomerular structure in streptozotocin-induced diabetic rats

BACKGROUND/AIMS: The streptozotocin (STZ)-induced diabetic rat is a widely used animal model of human diabetic nephropathy. In this model, diabetic nephropathy progresses without significant elevation in blood pressure. Therefore, studies have examined the effect of hypertension in STZ spontaneously hypertensive rats (SHR). This study investigated angiotensin II (Ang II)-induced hypertension in diabetic nephropathy in the STZ-diabetic rat independent of deleterious genetic effects in SHR. METHODS: Animals were divided as follows: nondiabetic controls (ND; n = 18); diabetic (STZ: 65 mg/kg; n = 16); Ang II-induced hypertensive ND (Ang II: 120 ng/kg/min; n = 9), and hypertensive diabetic rats (n = 18). Systolic blood pressure was measured by the tail-cuff method prior to STZ injection and then weekly. After 3 months, plasma creatinine, and 24-hour urine albumin and creatinine were measured and kidneys harvested for morphometry. RESULTS: Ang II infusion increased systolic blood pressure in diabetic and ND rats. When combined with diabetes, Ang II increased albumin excretion rate (14-fold, p < 0.05), plasma creatinine (1.5-fold, p < 0.005) worsened creatinine clearance (37%, p < 0.002) and increased glomerular basement membrane width (1.2-fold, p < 0.0001). CONCLUSION: Ang II caused moderate hypertension and accelerated diabetic nephropathy and glomerular structural changes. The Ang II-infused STZ-diabetic rat is an excellent model to study the deleterious glomerular effects of hypertension on diabetes independent of genetic traits.     

Salutary effect of pigment epithelium-derived factor in diabetic nephropathy: evidence for antifibrogenic activities

Diabetic nephropathy is a major complication of diabetes and a leading cause of end-stage renal diseases in the U.S. Pigment epithelium-derived factor (PEDF) is a potent angiogenic inhibitor that has been extensively studied in diabetic retinopathy. Recently, we reported that PEDF is expressed at high levels in normal kidneys and that PEDF levels are decreased in kidneys of streptozotocin (STZ)-induced diabetic rats. In the present study, we injected STZ-diabetic rats with an adenovirus expressing PEDF (Ad-PEDF) to evaluate its effects in diabetes. The results showed that increased expression of PEDF in the kidney in response to Ad-PEDF delivery significantly alleviated microalbuminuria in early stages of diabetes. Administration of Ad-PEDF was found to prevent the overexpression of two major fibrogenic factors, transforming growth factor-beta (TGF-beta)1 and connective tissue growth factor (CTGF), and to significantly reduce the production of an extracellular matrix (ECM) protein in the diabetic kidney. Moreover, PEDF upregulated metalloproteinase-2 expression in diabetic kidney, which is responsible for ECM degradation. In cultured human mesangial cells, PEDF significantly inhibited the overexpression of TGF-beta1 and fibronectin induced by angiotensin II. PEDF also blocked the fibronectin production induced by TGF-beta1 through inhibition of Smad3 activation. These findings suggest that PEDF functions as an endogenous anti-TGF-beta and antifibrogenic factor in the kidney. A therapeutic potential of PEDF in diabetic nephropathy is supported by its downregulation in diabetes; its prevention of the overexpression of TGF-beta, CTGF, and ECM proteins in diabetic kidney; and its amelioration of proteinuria in diabetic rats following Ad-PEDF injection.     

Reduction by tranexamic acid of glomerular hypertrophy and increased glomerular expression of extracellular matrix components induced by streptozotocin diabetes in rats

Background. Diabetic nephropathy is histologically characterized by expansion of the glomerular mesangium because of an increase in extracellular matrix (ECM) proteins (fibronectin and type IV (α2) collagen). Transforming growth factor-β1 (TGF-β1) is considered one of the major cytokines involved in the regulation of ECM synthesis and degradation. TGF-β1 is synthesized as an inactive precursor protein and then converted to its active form by proteolytic enzymes such as plasmin. In the present study we examined the effect of tranexamic acid (TA), a plasmin inhibitor, on ECM accumulation in glomeruli of rats with diabetic nephropathy. Methods. The effects of TA were examined by measuring various markers, including changes in kidney weight, albuminuria, glomerular volume, and the expression of glomerular ECM components (fibronectin, type IV (α2) collagen, and TGF-β1) in four groups of rats. The groups were: controls; control rats treated with TA; rats with streptozotocin-induced diabetes (STZ-rats), and STZ-rats treated with TA. Results. Oral administration of TA (300 mg/kg) twice a day had no effect on kidney weight, albuminuria, or glomerular volume in control rats, whereas it caused a slight increase in fibronectin mRNA and a slight decrease in type IV (α2) collagen and TGF-β1 mRNAs. In STZ-rats, TA significantly decreased all the above markers (glomerular volume, 0.96 ± 0.04 × 10⁶μm³ in STZ vs 0.69 ± 0.04 × 10⁶μm³ in STZ + TA: kidney weight, 3.7 ± 0.6 g in STZ vs 3.4 ± 0.6 g in STZ + TA). TA treatment did not influence glucose levels or body weight in either the control rats or the STZ-rats. Conclusions. In contrast to results of a report showing exacerbation of human diabetic retinopathy in patients treated with TA, our findings showed that TA may have a beneficial effect on diabetic nephropathy in STZ-diabetic rats. Received: September 13, 2000 / Accepted: February 28, 2001     

Protective effects of leflunomide on renal lesions in a rat model if diabetic nephropathy

Diabetic nephropathy is one of the most common chronic complications of diabetes with poor efficacy of clinical treatment. This study investigated the protective effects of leflunomide, a new immunosuppressant, on tubulointerstitial lesions in a rat model of diabetic nephropathy. Diabetes was induced with streptozotocin (STZ, 50?mg/kg) by intraperitoneal injection in male Wistar rats. Two weeks after STZ injection, diabetic rats were treated daily for 8 weeks with low (5?mg/kg) and high dose (10?mg/kg) of leflunomide, and benazepril hydrochloride (4?mg/kg) as a positive control. In diabetic rats, the 24-h urine volume, urine protein and microalbumin, blood creatinine and urea nitrogen significantly increased, which were attenuated by leflunomide treatment in a dose-dependent manner (all p?相似文献   

Nephropathy in model combining genetic hypertension with experimental diabetes. Enalapril versus hydralazine and metoprolol therapy

We compared the effects of the angiotensin-converting enzyme inhibitor enalapril and a conventional antihypertensive regimen (hydralazine and metoprolol) on kidney function, albuminuria, and glomerular ultrastructure in hypertensive diabetic and nondiabetic rats. Diabetes was induced with streptozocin at 8 wk of age in spontaneously hypertensive (SHR) rats. Antihypertensive drugs were administered in drinking water from the time of induction of diabetes in all groups. Blood pressure reduction was equal in the diabetic and nondiabetic SHR rats receiving either enalapril or hydralazine plus metoprolol. In diabetic SHR rats, there was a rise in serum creatinine after 32 wk, which did not occur in diabetic rats treated with either antihypertensive regimen or in nondiabetic rats. Both drug regimens reduced albuminuria in diabetic and nondiabetic SHR rats to a similar degree. Enalapril and the combination of hydralazine and metoprolol were associated with decreased glomerular basement membrane thickness and glomerular volume in diabetic and nondiabetic SHR rats without significant effect on fractional mesangial volume. Thus, antihypertensive therapy retards the development of albuminuria, glomerular basement membrane thickening, and glomerular hypertrophy in the rat in the presence or absence of diabetes. No specific benefit of angiotensin-converting enzyme inhibition was observed in these hypertensive models of nephropathy. Human studies comparing the effects of different classes of antihypertensive drugs on kidney function, proteinuria, and glomerular morphology are warranted.     

Delayed treatment with human umbilical cord blood-derived stem cells attenuates diabetic renal injury

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. Excess accumulation of extracellular matrix and the epithelial-to-mesenchymal transition contribute to renal fibrosis, which is associated with DKD. The present study examined whether delayed treatment with human umbilical cord blood-derived stem cells (hUCB-SC) showed a therapeutic effect on DKD progression. Experimental diabetes was induced by intraperitoneal injection of streptozotocin (STZ; 50 mg/kg) into 6-week-old male Sprague-Dawley rats. Age-matched control rats received an equivalent volume of sodium citrate buffer alone. At 4 weeks after the STZ injection when diabetic renal injury had developed, hUCB-SC were administered (1 × 10⁶ cells/rat) through the tail vein. Four weeks after administering the hUCB-SC, rats were sacrificed and we measured indices of DKD, including urinary protein excretion as well as fibronectin, α-smooth muscle actin (α-SMA), and E-cadherin mRNA, and protein expression. Diabetic rats developed significantly increased urinary protein excretion and renal hypertrophy compared to those in control rats. Renal expression of fibronectin and α-SMA mRNA, and protein were increased significantly in diabetic rats compared to those in the controls. E-cadherin protein expression in diabetic kidneys decreased significantly. Intravenously administered hUCB-SC effectively reduced proteinuria, renal fibronectin, and α-SMA up-regulation, as well as renal E-cadherin down-regulation in diabetic rats without a significant effect on blood glucose. Engrafted hUCB-SC in diabetic kidneys were confirmed by human DNA PKcs. The results demonstrated that delayed treatment with hUCB-SC attenuated the progression of diabetic renal injury.     

Roles of connective tissue growth factor and prostanoids in early streptozotocin-induced diabetic rat kidney: the effect of aspirin treatment

Background. Connective tissue growth factor (CTGF) is a cysteine-rich growth factor induced by transforming growth factor-β (TGF-β) and is thought to play a critical role in TGF-β-stimulated extracellular matrix accumulation. To explore its involvement in early diabetic nephropathy, we investigated the time course of CTGF gene expression and its regulation in streptozotocin (STZ)-induced diabetic rat kidney. Methods. Northern blot analysis for CTGF, TGF-β, and fibronectin expression was performed in the glomeruli of STZ-induced diabetic rats from 3 days to 12 weeks after the induction of diabetes, together with histological examination. To investigate the role of prostanoids in this process, aspirin was administered in one group of diabetic rats. Furthermore, CTGF expression was analyzed in rat mesangial cells cultured under high-glucose conditions. Results. Glomerular expression of CTGF and TGF-β1 mRNA was coordinately upregulated as early as day 3, followed by fibronectin induction and mesangial matrix accumulation. Chronic aspirin treatment in diabetic rats significantly attenuated mesangial expansion, and effectively suppressed CTGF induction, as well as inhibiting the upregulation of TGF-β1 and fibronectin expression. In cultured mesangial cells, aspirin treatment abolished high glucose-stimulated CTGF upregulation. Conclusions. These results indicate that CTGF expressed in the glomeruli is upregulated in the early stage of STZ-induced diabetic nephropathy in rats, and could be a critical mediator of the development of diabetic glomerulosclerosis. In addition, the modulatory effects of aspirin during this process suggest a role of the cyclooxygenase pathway in the progression of diabetic nephropathy. Received: March 5, 2002 / Accepted: December 6, 2002 Acknowledgments We thank Ms. A. Wada, Ms. J. Nakamura, and Ms. Y. Oki for technical assistance, and Ms. S. Doi and Ms. A. Sonoda for secretarial assistance. This work was supported in part by research grants from the Japanese Ministry of Education, Science, Sports and Culture; the Japanese Ministry of Health and Welfare; “Research for the Future (RFTF)” of the Japan Society for the Promotion of Science; the Ono Foundation for Medical Research; the Smoking Research Foundation; and the Salt Science Research Foundation. Correspondence to:M. Mukoyama     

Kidney involvement in a nongenetic rat model of type 2 diabetes

BACKGROUND: Rats fed a high fat diet and given a low dose of streptozotocin (STZ) (35 mg/kg) develop type 2 diabetes with insulin resistance, hyperinsulinemia, moderate hyperglycemia, hyperlipidemia, and salt-sensitive hypertension. We postulated that rats with noninsulinopenic (type 2) diabetes develop lesions of diabetic nephropathy significantly more prominent than those seen in classic insulinopenic (type 1) diabetic rats. METHODS: Rats were fed regular chow or high fat diet (60% calories from fat and 70% animal fat). After 5 weeks, rats fed regular chow received vehicle (controls) or 55 mg/kg STZ (type 1 diabetes mellitus). Rats fed high fat diet received vehicle (high fat) or low dose STZ, 35 mg/kg (type 2 diabetes mellitus). Rats were sacrificed 14 weeks after STZ/vehicle injection. RESULTS: Blood glucose, systolic blood pressure, and urinary protein excretion were significantly higher in both diabetes groups than in controls. Serum insulin levels (ng/mL) were higher in type 2 diabetes than in type 1 diabetes groups (0.49 +/- 0.12 vs. 0.07 +/- 0.07) (P= 0.01). Percentage of sclerosed glomeruli was significantly higher in type 2 diabetes group than in control and type 1 diabetes groups. Fibronectin expression was significantly increased in high fat, type 1 and type 2 diabetes groups compared to controls. The expression of type IV collagen, connective tissue growth factor (CTGF), and transforming growth factor-beta (TGF-beta) was significantly increased in high fat and type 2 diabetes groups compared to controls. CONCLUSION: Rats fed a high fat diet and given a low dose of STZ developed diabetes (with normal/high insulin levels), hypertension, and proteinuria. Kidney lesions in this type 2 model appear to be more pronounced than in type 1 diabetic rats despite lower blood glucose levels and proteinuria. We present a nongenetic rat model of type 2 diabetes mellitus and nephropathy.     

Blockade of renin-angiotensin system ameliorates renal injury in NIDDM model rats

Background. Recently, inhibition of the renin-angiotensin system has been reported to be effective for patients with diabetic nephropathy. In this study, we examined the renal protective effects of candesartan cilexetil (TCV-116) in Wistar fatty rats, a model of non-insulin-dependent diabetes mellitus (NIDDM) with renal injuries. Methods. Twelve-week-old Wistar fatty rats received candesartan cilexetil (0.3 or 1 mg/kg) or enalapril (10 mg/kg) daily, administered orally, for 16 weeks. Routine laboratory parameters, such as urinary albumin and total protein excretion, were measured every 4 weeks, and renal function tests and histopathological studies were carried out at the end of the experiment. Results. In the 12-week-old Wistar fatty rats, plasma glucose and insulin levels were significantly higher than those in age-matched Wistar lean rats (normal controls). Urinary albumin and total protein excretion was slightly but significantly increased as compared to these parameters in Wistar lean rats, and increased further with time. Daily administration of candesartan cilexetil or enalapril inhibited the increase in urinary albumin and total protein excretion without affecting plasma glucose and insulin levels. In histopathological studies, candesartan cilexetil (0.3 and 1 mg/kg) and enalapril (10 mg/kg) prevented the glomerular injury observed in vehicle-treated rats. Candesartan cilexetil (1 mg/kg) and enalapril also inhibited tubular changes. Systolic blood pressure in the drug-treated groups was significantly decreased compared with that in vehicle-treated rats. Conclusions. Inhibitors of the renin-angiotensin system ameliorated proteinuria and the pathological changes of renal injuries in this NIDDM model. Candesartan cilexetil may be useful for the treatment of NIDDM patients with renal damage. Received: March 1, 1999 / Accepted: June 13, 2000     

Effects of endothelin receptor antagonists on the progression of diabetic nephropathy

BACKGROUND: Diabetic nephropathy is the leading cause of end-stage renal disease in European countries and is associated with an enhanced renal synthesis of endothelin (ET)-1. ETs are - beside their potent vasoconstrictor properties - very potent profibrotic acting paracrine hormones especially in the kidney. METHODS: We analyzed in rats with streptozotocin-induced diabetes the effects of an ETA-type (ETA) receptor antagonist (LU 135252) in comparison to a combined ETA/ETB receptor antagonist (LU 224332) on the expression of interstitial and glomerular collagen type I, III and IV as well as on fibronectin and laminin by quantitative immunohistochemistry using a computer-aided image analysis system. Global glomerular matrix deposition was analyzed after PAS staining. In addition to the morphometric examination of the kidneys, we also investigated GFR, urinary albumin and total protein excretion. The diabetic rats were treated for 36 weeks. RESULTS: Treatment with either LU 135252 or LU 224332 normalized the amount of PAS-positive material within the glomeruli. The expression of glomerular fibronectin and type IV collagen was increased 36 weeks after induction of diabetes. The overexpression of these two matrix proteins within the glomeruli of diabetic rats was completely abolished by both ET receptor antagonists, whereas protein excretion was only reduced by about 50% as compared to diabetic rats without treatment. CONCLUSION: The present study indicates that ETA receptor antagonists as well as combined ETA/ETB receptor antagonists reduce proteinuria and completely normalize the renal matrix protein expression in hyperglycemic rats with streptozotocin-induced diabetes. The antifibrotic effect seems to be mediated via the ETA receptor. ET receptor antagonists might be a new approach in the treatment of diabetic nephropathy.     

The Puerarin improves renal function in STZ-induced diabetic rats by attenuating eNOS expression

Abstract

Diabetic nephropathy (DN) is a serious complication and it leads to kidney failure. The endothelial nitric oxide synthases (eNOS) seems to be involved in the development and progression of DN. The Puerarin is a well-known Chinese traditional formula, which is widely used in clinical practice for the treatment of kidney disease. The present study was designed to investigate the renal protective effects of Puerarin on streptozotocin (STZ)-induced diabetic rats. Thirty Sprague–Dawley (SD) male rats were divided into three groups at random. The diabetic group and the Puerarin-treated group were intraperitoneally injected with STZ 65?mg/kg and the Puerarin-treated rats were intraperitoneally injected Puerarin 100?mg/kg/day for 4 weeks. The results showed the Puerarin could improve body weight, blood sugar, BUN and SCr levels, and reduce ultrastructural changes of kidney in diabetic rats. It also attenuated eNOS expression in glomerular endothelial cells and tubular cells of diabetic rats with Puerarin treatment (p?<?0.05). The Puerarin had significant renal-protective effects for the diabetic nephropathy, possibly through regulating eNOS expression, and it may be used as a potential therapeutic reagent.     

GAS6 intron 8 c.834 + 7G > A gene polymorphism in diabetic nephropathy

Abstract

Background - Aim: In animal experiments, growth arrest-specific 6 (Gas6) protein plays a key role in the development of mesangial cell and glomerular hypertrophy in the early phase of diabetic nephropathy, and diabetic nephropathy is prevented by warfarin-induced inhibition of GAS6 protein. It was shown that GAS6 intron 8 c.834?+?7G?>?A polymorphism is protective against type 2 diabetes mellitus, and AA genotype is associated with higher blood levels of GAS6 protein. Our aim is to investigate whether this polymorphism is a risk factor for diabetic nephropathy in type 2 diabetes mellitus. Method: Eighty-seven patients with diabetic nephropathy were compared with 66 non-diabetic controls in terms of GAS6 intron 8 c.834?+?7G?>?A polymorphism. Patients with history of stroke, ischemic heart disease were excluded. Each patient was examined by the ophthalmologist to determine diabetic retinopathy. Results: Frequency of GG, GA and AA genotypes are similar in diabetic nephropathy and control groups according to GAS6 intron 8 c.834?+?7G?>?A polymorphism (p?=?0.837). Rate of diabetic retinopathy was 54.02%. In the subgroup analysis, GA genotype was significantly more frequent than GG genotype in patients with diabetic retinopathy when compared to without diabetic retinopathy (p?=?0.010). Conclusion: In our study, GAS6 intron 8 c.834?+?7G?>?A polymorphism was not associated with diabetic nephropathy in type 2 diabetes mellitus. However, heterozygous state of this polymorphism may be a risk factor for diabetic retinopathy in patients with diabetic nephropathy.     

Nondiabetic Renal Disease in Type 2 Diabetic Patients: A Review of our Experience in 220 Cases

Background: The purpose of this retrospective study was to evaluate the renal biopsies performed on type 2 diabetic patients for suspicion of nondiabetic renal disease (NDRD) and to correlate the pathological finding with the clinical and laboratory findings. Methods: From January 1999 to December 2009, 220 people with type 2 diabetes for clinically suspected NDRD underwent renal biopsy. The case records of these patients were retrospectively analyzed. Based on the biopsy findings, patients were divided into two groups: Group I, isolated diabetic glomerulosclerosis (DGS), and Group II, NDRD with underlying DGS. Clinical and laboratory data were analyzed in relation to the histopathological findings. Results: Of the 220 patients studied, 153 were males and 67 were females. The average age was 51.35 years (30–79). Renal biopsy showed that 100 patients (45.5%) had NDRD with underlying DGS. Group II had a significantly higher level of proteinuria and hematuria but less frequent diabetic retinopathy. There was no significant difference between the two groups in age, duration of diabetes, presence of hypertension, serum creatinine, and glomerular filtration rate. IgA nephropathy was the most common, accounting for 34% of Group II, membranous nephropathy ranked second accounting for 22.0%, followed by mesangial proliferative nephritis for 14%. Conclusion: This study showed that IgA nephropathy is the commonest NDRD among diabetics. The absence of retinopathy, especially when associated with nephritic proteinuria and hematuria, strongly predicts NDRD superimposed on DGS. Renal biopsy should be performed in diabetics when the clinical scenario is atypical.     

Effects of insulin-dependent diabetes mellitus on perforator-based flaps in streptozotocin diabetic rats

The purpose of this study was to investigate the effects of insulin-dependent diabetes mellitus (IDDM) on the viability of perforator-based flaps (pbf) in diabetic rats. Random-pattern flaps were also used as a control flap group. Wistar Albino rats, female, n = 60, were used. The study was done with four groups: Group 1 (diabetic rats, pbf), Group 2 (non-diabetic rats, pbf), Group 3 (diabetic rats, McFarlane flap), and Group 4 (non-diabetic rats, McFarlane flap). Streptozocin (STZ, 55 mg/kg) in a vehicle (sodium citrate, pH 4.5) was injected into the rats intraperitonally to create an IDDM model in the diabetic groups. Only the vehicle without STZ was injected into the rats intraperitonally in the non-diabetic groups. All flaps were elevated 10 weeks after injections. Measurements of the surviving areas of the flaps, and microangiographic and histopathologic studies were done 7 days after flap elevation. Blood glucose levels of the diabetic rats were significantly higher than those of the non-diabetic groups ( p < 0.001). The surviving flap areas were 41 +/- 21 percent in Group 1, 65 +/- 25 percent in Group 2, 49 +/- 10 percent in Group 3, and 66 +/- 10 percent in Group 4. The surviving flap areas of the diabetic groups were significantly less than those of the non-diabetic groups ( p < 0.001). Specific histopathologic changes of IDDM were seen only in the diabetic groups. Microangiographies in the diabetic and non-diabetic groups were very similar. The surviving flap areas of the perforator-based and random-pattern skin flaps in the diabetic rats were decreased by IDDM. If a flap is planned for diabetic wounds, it should be kept in mind that the area of flap necrosis may be larger than those of non-diabetics.     

Autoregulation of renal blood flow in streptozocin-induced diabetic rats

Autoregulation of renal blood flow (RBF) was studied in male Wistar rats. We studied 11 control rats, 11 rats with severe streptozocin (STZ)-induced hyperglycemia (diabetic group), and 10 moderately hyperglycemic rats made diabetic by injection of STZ but given 2-8 U s.c. insulin daily (insulin-treated group). RBF was measured by an electromagnetic flowmeter during stepwise reduction of renal perfusion pressure 4-8 wk after injection of STZ (older group). RBF autoregulation of the diabetic group was impaired compared with the control group. In the insulin-treated group, autoregulatory capability was less attenuated than in the diabetic group. The average autoregulatory index (ARI) of the diabetic group (0.61 +/- 0.05) was greater than that of the control (0.24 +/- 0.02, P less than .01) and the insulin-treated (0.33 +/- 0.07, P less than .05) groups. To study the relationship between autoregulation and the duration of diabetes, an autoregulatory study was also made in a group of 22 rats (11 diabetic and 11 control) that were tested 2-3 wk after injection of STZ (younger group). The ARI in the younger diabetic group was smaller than that in the older diabetic group (P less than .05). The results suggest that in uncontrolled diabetes RBF fluctuates with blood pressure change, and protection against hypertensive injury of glomerular capillaries may be diminished. Autoregulatory disability develops with time, and insulin treatment diminishes impairment of autoregulation. These findings may also explain the adverse consequences of hypertension on the progression of diabetic nephropathy in poorly controlled diabetes.     

Pyridoxal phosphate prevents progression of diabetic nephropathy.

BACKGROUND: We have demonstrated that pyridoxal 5'-phosphate (PLP), an active form of vitamin B6, inhibits formation of advanced glycation end-products (AGEs) by trapping 3-deoxyglucosone. The present study aimed to clarify if PLP could exert beneficial effects on nephropathy in diabetic rats. METHODS: Streptozotocin (STZ)-induced diabetic rats were treated by oral administration of PLP or pyridoxamine (PM), another active form of vitamin B6, at a dose of 600 mg/kg/day for 16 weeks. AGEs [imidazolone, N(epsilon)-(carboxymethyl)lysine (CML) and N(2)-carboxyethyl-2'-deoxyguanosine (CEdG)], transforming growth factor-beta1 (TGF-beta1), type 1 collagen and fibronectin were detected in the kidneys using immunohistochemistry. Gene expression of TGF-beta1 and receptor for AGEs (RAGEs) in the kidneys was determined using real-time quantitative polymerase chain reaction. RESULTS: Administration of PLP significantly inhibited albuminuria, glomerular hypertrophy, mesangial expansion, and interstitial fibrosis as compared with diabetic rats. PLP markedly inhibited accumulation of AGEs such as imidazolone, CML and CEdG, a DNA-linked AGE, in glomeruli. PLP significantly inhibited expression of TGF-beta1, type 1 collagen, fibronectin and RAGE in the kidneys. PLP was superior to PM in inhibiting accumulation of AGEs, expression of TGF-beta1, type 1 collagen, and fibronectin, and the development of diabetic nephropathy. CONCLUSIONS: PLP prevented progression of nephropathy in STZ-induced diabetic rats by inhibiting formation of AGEs. PLP is considered a promising active form of vitamin B6 for the treatment of AGE-linked disorders such as diabetic nephropathy.     

厄贝沙坦联合降糖保肾方治疗早期糖尿病肾病大鼠的实验研究

目的：探讨中西医结合对早期糖尿病肾病大鼠肾脏氧化应激与超微结构变化的影响。方法：用链脲佐菌素（STZ）诱导糖尿病肾病大鼠模型,将SD大鼠随机分成5组,每组10只：正常对照组（C组）、糖尿病肾病组（D组）、厄贝沙坦组（X组）、降糖保肾方组（Z组）和中西医结合组（L组）。5周末检测5组大鼠血糖（BG）、糖化血红蛋白（HbA1c）、总胆固醇（TC）、三酰甘油（TG）、血尿素氮（BUN）、肌酐（Scr）、肌酐清除率（Ccr）、肾重／体重（S／T）、尿白蛋白排泄率（UAER）等指标的变化以及肾皮质总超氧化物歧化酶（TSOD）、过氧化氢酶（CAT）的活性、丙二醛（MDA）的水平;利用透射电子显微镜观察肾脏足细胞超微病理结构。结果：D组与C组比较,BG、HbA1c、TC、TG、S／T明显升高;BUN、Scr水平差异无统计学意义,但Ccr显著下降;抗氧化酶中,TSOD、CAT活性明显下降,MDA水平明显升高;UAER增高,足细胞足突严重融合。中药或西药单药治疗组上述指标改善,尤其中西医结合治疗组上述指标改善显著,明显优于各单药治疗组。结论：早期糖尿病肾病大鼠肾脏即存在氧化应激增加及足细胞的损害,厄贝沙坦联合中药方剂降糖保肾方对糖尿病肾脏的保护作用优于单种给药治疗,其机制部分与其对糖尿病肾组织氧化应激增加、足细胞损伤与协同抑制作用有关。