OBJECTIVES: To investigate the therapeutic mechanism of Danzhi Jiangtang Capsule (DZJTC) for repairing renal vascular endothelial injury in rats with diabetic nephropathy (DN). METHODS: Fifty male SD rat models of DN, established by left nephrectomy, high-sugar and high-fat diet and streptozotocin injection, were randomized into DN model group, low-, medium-, and high-dose DZJTC treatment groups, and DAPT (a γ-secretase inhibitor) treatment group, with 10 rats with normal feeding as the control group. DZJTC was administered by daily gavage at 0.315, 0.63, or 1.26 g/kg, and DAPT (20 mg/kg, dissolved in 50% CMC-Na solution) was given by gavage every other day for 4 weeks; normal saline was given in the control and model groups. After treatment, the levels of creatinine (CRE), blood urea nitrogen (BUN), and microalbuminuria (mALB) were detected with ELISA, and renal pathologies were observed by transmission electron microscopy. Renal expressions of vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) were measured by immunohistochemistry, and the protein expressions of CD31 and Notch signaling pathway components were detected using Western blotting. RESULTS: The rat models of DN showed significantly increased CRE, BUN, and mALB levels, obvious renal pathologies under electron microscopy, increased renal VEGF, ET-1 and CD31 expressions, and upregulated Notch1, NICD, and MAML1 protein levels. Treatment with DZJTC at the 3 doses and DAPT significantly reduced CRE, BUN, and mALB levels, improved renal pathology, decreased VEGF, ET-1 and CD31 expressions, and lowered Notch1, NICD and MAML1 levels, and the effects were the most pronounced with high-dose DZJTC. CONCLUSIONS DZJTC ameliorates hyperproliferation and dysfunction of renal vascular endothelium in DN rats possibly by regulating renal VEGF and ET-1 levels via inhibiting NICD- and MAML1-mediated Notch signaling pathway.
Animals ; Male ; Drugs, Chinese Herbal/therapeutic use* ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects* ; Diabetic Nephropathies/drug therapy* ; Receptor, Notch1/metabolism* ; Kidney/blood supply* ; Diabetes Mellitus, Experimental ; Down-Regulation ; Endothelium, Vascular/metabolism* ; Nuclear Proteins/metabolism*

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus, which is characterized in renal tubulointerstitial fibrosis (TIF). The current study was designed to investigate the protective effect of Jujuboside A (Ju A) on TIF in type 2 diabetes (T2DM) mice, and explore its underlying anti-fibrosis mechanism. A mouse T2DM model was established using high fat diet (HFD) feeding combined with intraperitoneal injection of streptozotocin (STZ). Then, diabetic mice were treated with Ju A (10, 20 and 40 mg·kg^-1·d^-1, i.g.) for 12 weeks. Results showed that administration of Ju A not only down-regulated fasting blood glucose (FBG) levels, but also improved hyperlipidemia and renal function in diabetic mice. Moreover, the reduced ECM accumulation was observed in the renal cortex of Ju A treated diabetic mice, while the TIF progression was also attenuated by Ju A through blocking the epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells (RTECs). Further mechanism studies showed that Ju A treatment effectively down-regulated the protein expression and subsequent nuclear translocation of Yin Yang 1 (YY1) in the renal cortex of diabetic mice, and reduced the levels of transforming growth factor-β1 (TGF-β1) in the serum and renal cortex of Ju A treated mice. According to invitro studies, the up-regulated YY1/TGF-β1 signaling pathway was restored by Ju A in high glucose (HG) cultured HK-2 cells. Taken together, these findings demonstrated that Ju A can ameliorate the TIF of DN through down-regulating the YY1/TGF-β1 signaling pathway.
Animals ; Blood Glucose ; Diabetes Mellitus, Experimental/metabolism* ; Diabetes Mellitus, Type 2/drug therapy* ; Diabetic Nephropathies/metabolism* ; Fibrosis ; Mice ; Saponins ; Signal Transduction ; Streptozocin ; Transforming Growth Factor beta1/metabolism*

Diabetic kidney disease is a microvascular complication of diabetes mellitus and the leading cause of end-stage renal disease resulting in renal replacement therapy. Approximately 30% to 40% of diabetic patients have diabetic kidney disease, which contributes to a significant increase in morbidity and mortality. Microalbuminuria is considered the gold standard for diabetic kidney disease diagnosis; however, its predictive value is restricted. Although blood glucose control, blood pressure control, and angiotensin converting enzyme inhibitors have been the primary treatment strategies, there are no definitive treatment modalities capable of inhibiting the progression of kidney dysfunction in these patients. This study was undertaken to answer seven questions regarding the various aspects of diabetic kidney disease. Why does it develop? what kind of factors affect its development? How is it diagnosed? What are its possible biomarkers? When is a kidney biopsy necessary? What are the preventive and therapeutic options? And what are the novel treatments?
Angiotensin-Converting Enzyme Inhibitors ; Biomarkers ; Biopsy ; Blood Glucose ; Blood Pressure ; Diabetes Mellitus ; Diabetic Nephropathies ; Diagnosis ; Humans ; Kidney ; Kidney Failure, Chronic ; Mortality ; Renal Replacement Therapy

Early intervention in patients with diabetes may slow the progression of kidney disease, and early recognition of renal impairment is critical to achieving optimal patient outcomes. Annual screening for the presence of albuminuria in diabetic patients is necessary to prevent diabetic neuropathy. Selection of the appropriate medication to control blood glucose and blood pressure is also important. In addition, however, patients should be willing to manage themselves to overcome diabetic kidney disease through lifestyle changes such as diet, smoking, and weight management, and restrictions on private therapies.
Albuminuria ; Blood Glucose ; Blood Pressure ; Diabetic Nephropathies ; Diabetic Neuropathies ; Diet ; Early Intervention (Education) ; Humans ; Kidney Diseases ; Life Style ; Mass Screening ; Self Care ; Smoke ; Smoking

BACKGROUND: Microalbuminuria (MA) is a predictor for diabetic nephropathy and mortality of cardiovascular disease. Diabetic nephropathy can be prevented by blood glucose and blood pressure control. Koreans have been found to have a significantly higher risk of type 2 diabetes than Caucasians, despite having normal weights. It is necessary to consider obesity status in the prevention of type 2 diabetes. This study aimed to determine the relationship between MA and hypertension according to obesity status in prediabetes.METHODS: This study was retrospectively conducted in 1,183 prediabetes, aged 30-70 years with fasting blood glucose levels of 100-125 mg/dL or hemoglobin A1c levels of 5.7–6.4% who health examinees at 16 health promotion centers from 2015 to 2016. Study subjects were classified according to obesity and hypertension. Obesity is defined as body mass index of ≥25 kg/m². Blood pressure was categorized as follows: normal blood pressure, <120/80 mmHg; prehypertension, 120–139/80–89 mmHg; and hypertension, ≥140/90 mmHg. We analyzed the relationship between MA and hypertension according to obesity using multivariable logistic regression analysis.RESULTS: While both prehypertensive and hypertensive subgroups were significantly associated with MA in the nonobese, the hypertensive subgroup was only associated with MA in the obese. In the combined effects of obesity and hypertension, prediabetes with normal weight and hypertension had the highest risk of MA (adjusted odds ratio, 6.39; 95% confidence interval, 2.90–14.10) compared to those with nonobese and normal blood pressure.CONCLUSIONS: Our findings suggest that nonobese prediabetes with hypertension would need to be more concerned about MA than do obese prediabetes with hypertension.
Albuminuria ; Blood Glucose ; Blood Pressure ; Body Mass Index ; Cardiovascular Diseases ; Diabetic Nephropathies ; Fasting ; Health Promotion ; Hypertension ; Logistic Models ; Mortality ; Obesity ; Odds Ratio ; Prediabetic State ; Prehypertension ; Retrospective Studies ; Weights and Measures

BACKGROUND: This study investigated the overall status of diabetes control and screening for diabetic microvascular complications in patients with type 2 diabetes mellitus attending primary care clinics in Korea. METHODS: In this cross-sectional observational study, 191 primary care clinics were randomly selected across Korea from 2015 to 2016. In total, 3,227 subjects were enrolled in the study. RESULTS: The patients followed at the primary care clinics were relatively young, with a mean age of 61.4±11.7 years, and had a relatively short duration of diabetes (mean duration, 7.6±6.5 years). Approximately 14% of subjects had diabetic microvascular complications. However, the patients treated at the primary care clinics had suboptimal control of hemoglobin A1c levels, blood pressure, and serum lipid levels, along with a metabolic target achievement rate of 5.9% according to the Korean Diabetes Association guidelines. The screening rates for diabetic nephropathy, retinopathy, and neuropathy within the past 12 months were 28.4%, 23.3%, and 13.3%, respectively. CONCLUSION: The overall status of diabetes management, including the frequency of screening for microvascular complications, was suboptimal in the primary care clinics. More efforts should be made and more resources need to be allocated for primary care physicians to promote adequate healthcare delivery, which would result in stricter diabetes control and improved management of diabetic complications.
Blood Pressure ; Delivery of Health Care ; Diabetes Complications ; Diabetes Mellitus, Type 2 ; Diabetic Nephropathies ; Humans ; Korea ; Mass Screening ; Observational Study ; Physicians, Primary Care ; Primary Health Care ; Tertiary Care Centers

BACKGROUND: Removal of uremic toxins such as indoxyl sulfate by AST-120 is known to improve renal function and delay the initiation of dialysis in patients with advanced chronic kidney disease. However, it is unclear whether the addition of AST-120 to conventional treatments is effective in delaying the progression of renal dysfunction in patients with diabetic nephropathy. METHODS: A total of 100 patients with type 2 diabetes and renal dysfunction (serum creatinine levels ranging from 1.5 to 3.0 mg/dL) were recruited from eight centers in Korea and treated with AST-120 (6 g/day) for 24 weeks. The primary endpoint was improvement in renal function measured as the gradient of the reciprocal serum creatinine level (1/sCr) over time (i.e., the ratio of 1/sCr time slope for post- to pre-AST-120 therapy). A response was defined as a ratio change of the regression coefficient of 1/sCr ≤ 0.90. RESULTS: Renal function improved in 80.3% of patients (61/76) after 24 weeks of AST-120 treatment. There were no differences between responder and non-responder groups in baseline characteristics except for diastolic blood pressure (73.5 ± 9.5 mmHg in the responder group vs. 79.3 ± 11.1 mmHg in the non-responder group; P = 0.046). Serum lipid peroxidation level decreased significantly in the responder group (from 2.25 ± 0.56 μmol/L to 1.91 ± 0.72 μmol/L; P = 0.002) but not in the non-responder group. CONCLUSION: The addition of AST-120 to conventional treatments may delay the progression of renal dysfunction in diabetic nephropathy. The antioxidant effect of AST-120 might contribute to improvement in renal function.
Antioxidants ; Blood Pressure ; Creatinine ; Diabetic Nephropathies ; Dialysis ; Humans ; Indican ; Korea ; Lipid Peroxidation ; Oxidative Stress ; Prospective Studies ; Renal Insufficiency, Chronic

OBJECTIVE: To explore the effect of "diabetes specialists-community general practitioners-community nurse co-management mode" and "diabetes specialist management mode" on diabetic nephropathy (DN) in primary medical institutions. METHODS: Patients with type 2 diabetes admitted to Quanzijie Health Clinic of Jimusar County of Xinjiang Uygur Autonomous Region from October 2017 to March 2018 were enrolled. The Patients were divided into co-management group or specialist management group according to their administrative villages. The treatment plans of the two groups were formulated with reference to the current guidelines. The subjects of the co-management group were jointly managed by a fixed team composed of diabetes specialists from Jimusar Traditional Chinese Medicine Hospital, community general practitioners and community nurses from Quanzijie Health Clinic, and required to attend diabetes education courses every month. The diabetes specialist of Jimusar Traditional Chinese Medicine Hospital was responsible for the formulation and management of the treatment plan of the research object. Follow-up was fulfilled once every 4 weeks for 24 weeks in two groups. Before and after intervention, blood glucose, blood pressure, urinary albumin/creatinine ratio (UACR), estimated glomerular filtration rate (eGFR) as well as the utilization rate of angiotensin converting enzyme inhibitors/angiotensin II receptor blocker (ACEI/ARB) were collected. RESULTS: A total of 115 patients accomplished this study with 54 patients in co-management group and 61 patients in specialist management group. After 24 weeks of intervention, fasting glucose level, postprandial glucose level 2 hours after breakfast, glycosylated hemoglobin (HbA1c), Log UACR in co-management group and specialists management group were significantly decreased compared with baseline [fasting glucose level (mmol/L): 8.06±1.92 vs. 9.16±2.83, 8.21±2.10 vs. 9.06±1.89; postprandial glucose level 2 hours after breakfast (mmol/L): 12.26±3.78 vs. 14.11±5.28, 12.47±3.63 vs. 14.00±3.88; HbA1c: 0.074±0.014 vs. 0.082±0.023, 0.076±0.014 vs. 0.081±0.016; Log UACR (mg/g): 1.63±1.56 vs. 2.25±1.44, 1.84±1.65 vs. 2.43±1.56, all P < 0.05], but there was no statistical significance between the two groups [fasting glucose level (mmol/L): -1.10±0.47 vs. -0.85±0.36, postprandial glucose level 2 hours after breakfast (mmol/L): -1.85±0.88 vs. -1.53±0.68, HbA1c: -0.008±0.004 vs. -0.006±0.003, Log UACR (mg/g): -0.61±0.29 vs. -0.59±0.29, all P < 0.05]. There were no significant changes in blood pressure, serum creatinine and eGFR in the two groups before and after intervention. There were 18 and 24 patients with hypertension in co-management group and specialist management group, respectively. The utilization rates of ACEI/ARB in both groups after intervention were significantly higher than those before intervention [88.9% (16/18) vs. 22.2% (4/18), 95.8% (23/24) vs. 29.2% (7/24), both P < 0.01]. At the end of the study, the utilization rate of ACEI/ARB was similar between the two groups [88.9% (16/18) vs. 95.8% (23/24), P > 0.05]. CONCLUSIONS Both "diabetes specialists-community general practitioners-community nurse co-management mode" and "diabetes specialist management mode" can effectively decrease glucose levels and UACR levels of patients with type 2 diabetes as well as the standard use of antihypertensive agents, which has positive effects on the prevention and treatment on DN.
Blood Glucose ; Creatinine ; Diabetes Mellitus, Type 2 ; Diabetic Nephropathies ; Humans ; Prospective Studies

Diabetic nephropathy (DN) is one of the common microvascular complications of diabetes mellitus. Renal fibrosis is closely related to the deterioration of renal function. The present study aimed to investigate protective effect of Taxus chinensis on high-fat diet/streptozotocin-induced DN in rats and explore the underlying mechanism of action. The rat DN model was established via feeding high fat diet for 4 weeks and subsequently injecting streptozotocin (30 mg·kg body weight) intraperitoneally. The rats with blood glucose levels higher than 16.8 mmol·L were selected for experiments. The DN rats were treated with Taxus chinensis orally (0.32, 0.64, and 1.28 g·kg) once a day for 8 weeks. Taxus chinensis significantly improved the renal damage, which was indicated by the decreases in 24-h urinary albumin excretion rate, blood serum creatinine, and blood urea nitrogen. Histopathological examination confirmed the protective effect of Taxus chinensis. The thickness of glomerular basement membrane was reduced, and proliferation of mesangial cells and podocytes cells and increase in mesangial matrix were attenuated. Further experiments showed that Taxus chinensis treatment down-regulated the expression of TGF-β1 and α-SMA, inhibited phosphorylation of Smad2 and Smad3. These results demonstrated that Taxus chinensis alleviated renal injuries in DN rats, which may be associated with suppressing TGF-β1/Smad signaling pathway.
Albumins ; Animals ; Blood Glucose ; metabolism ; Creatinine ; blood ; Diabetic Nephropathies ; blood ; drug therapy ; genetics ; urine ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Kidney ; drug effects ; metabolism ; Male ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; drug effects ; Smad Proteins ; genetics ; metabolism ; Taxus ; chemistry ; Transforming Growth Factor beta1 ; metabolism

OBJECTIVETo evaluate the renal protective effect of Tangshenkang Granule () in a rat model of diabetic nephropathy (DN).

METHODSForty male Sprague-Dawley rats were randomly divided into control, DN, Tangshenkang and benazepril groups. DN model was established in the rats of DN, Tangshenkang and benazepril groups. Tangshenkang Granule solution and benazepril hydrochloride solution were intragastrically administered daily to the rats in the Tangshenkang and benazepril groups for 8 weeks, respectively. Urinary albumin and creatinine were detected. The albumin/creatinine (ACR) was calculated in addition to 24 h urinary protein (24-h UPr), serum creatinine (Scr), blood urea nitrogen (BUN), total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and creatinine clearance rate (Ccr). Right kidneys were harvested for pathological observation using periodic acid-silver methenamine-Masson staining. The average glomerular diameter (DG), average glomerular (AG) and mesangial areas (AM) were measured. The thickness of glomerular basement membrane (TGBM) was detected using transmission electron microscope.

RESULTSCompared with rats in the control group, rats in the DN group showed significantly decreased body weight, increased hypertrophy index, 24-h urinary volume, 24-h UPr, ACR, Scr, BUN, Ccr, blood lipids as well as renal pathological indices including DG, AG, AM, AM/AG and TGBM (P <0.05). Compared with the DN group, the weights of rats in the Tangshenkang and benazepril groups were significantly increased, and the renal hypertrophy indices were significantly decreased (P <0.05). The 24-h urinary volumes, ACR, 24-h UPr, Scr, BUN, Ccr, LDL, DG, AG, AM and TGBM were obviously decreased (P <0.05). Compared with the benazepril group, the Tangshenkang group showed significantly decreased levels of ACR, 24-h UPr, AG and AM (P <0.05).

CONCLUSIONSTangshenkang Granule decreased the urinary protein, attenuated the high glomerular filtration rate and improved lipid metabolism in DN rats, and prevented further injury induced by diabetic nephropathy.

Albuminuria ; complications ; Animals ; Basement Membrane ; drug effects ; metabolism ; Blood Urea Nitrogen ; Body Weight ; drug effects ; Creatinine ; blood ; urine ; Diabetic Nephropathies ; blood ; drug therapy ; physiopathology ; urine ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Hypertrophy ; Kidney Function Tests ; Kidney Glomerulus ; drug effects ; pathology ; physiopathology ; Lipid Metabolism ; drug effects ; Lipids ; blood ; Male ; Rats, Sprague-Dawley