Ameliorative effect of white tea from 50-year-old tree of Camellia sinensis L. (Theaceae) on kidney damage in diabetic mice via SIRT1/AMPK pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic kidney damage (DKD) is one of the most common complications of diabetes, which is known as a chronic inflammatory kidney disease caused by persistent hyperglycemia. White tea was originally used as a folk medicine to treat measles in ancient China. What arouses our interest is that there is a traditional method to treat diabetes with white tea taken from over 30-year-old tree of Camellia sinensis L. However, there are few reports on the renal protection of white tea. AIM OF THE STUDY: This present study was designed to study the potential protective effects of white tea (WT) and old tree white tea (OTWT) on high-fat-diet (HFD) combined with streptozotocin (STZ)-induced type 2 diabetic mice to explore the possible mechanism of WT/OTWT against DKD. MATERIALS AND METHODS: C57BL/6 mice were randomly divided into four groups: NC, T2D, WT (400 mg/kg·b.w, p.o.), OTWT (400 mg/kg·b.w, p.o.). Diabetes was established in all groups except NC group, by six weeks of HFD feeding combined with STZ (50 mg/kg, i.p.) for 3 times, treatments were administered for six weeks and then all the animals were decapitated; kidney tissues and blood samples were collected for the further analysis, including: levels of insulin, lipid metabolism (TG, TC, HDL, LDL, FFA), antioxidative enzymes (catalase (CAT), super oxide dismutase (SOD), glutathione peroxidase (GPx)), blood urea nitrogen (BUN) and creatine, inflammatory cytokines (TNF-α, IL-1ß, COX-2, iNOS, MCP-1), advanced glycation end products (AGE), receptor of AGE (RAGE), Nrf2, AMPK, SIRT1, and PGC-1α. H&E, PAS and Masson staining were performed to examine the histopathological alterations of the kidneys. RESULTS: Our data showed that WT and OTWT reversed the abnormal serum lipids (TG, TC, HDL, LDL, FFA) in T2D mice, upregulated antioxidative enzymes levels (CAT, SOD, GPx) and inhibit the excessive production of proinflammatory mediators (including MCP-1, TNF-α, IL1ß, COX-2 and iNOS) by varying degrees, and OTWT was more effective. In histopathology, OTWT could significantly alleviate the accumulation of renal AGE in T2D mice, thereby improving the structural changes of the kidneys, such as glomerular hypertrophy, glomerular basement membrane thickening and kidney FIbrosis. CONCLUSIONS: Both WT and OTWT could alleviate the diabetic changes in T2D mice via hypoglycemic, hypolipidemic, anti-oxidative and anti-inflammatory effects, while OTWT was more evident. OTWT could prominently alleviate the accumulation of AGE in the kidneys of T2D mice, thereby ameliorating the renal oxidative stress and inflammatory damage, which was associated with the activation of SIRT1/AMPK pathway.

Restoration of Mimecan Expression by Grape Seed Procyanidin B2 Through Regulation of Nuclear Factor-kappaB in Mice With Diabetic Nephropathy.

Grape seed procyanidin B2 (GSPB2) exerts a variety of potent protective pharmacological effects on diabetic complications. The renal protective effects of GSPB2 and the target protein mimecan regulated by GSPB2, discovered in a previous quantitative proteomic analysis, were assessed in mice with diabetic nephropathy Twenty-four db/db mice were divided into 2 groups of the vehicle-treated and GSPB2-treated (30 mg/kg/d) diabetic groups. All animals were observed for 10 weeks. Treatment with GSPB2 resulted in an improvement in body weight increase and serum levels of triglyceride, total cholesterol, advanced glycation end products, and urinary albumin excretion in comparison with the vehicle-treated diabetic mice (P < .05), although these levels were still higher than those in the control group. Treatment with GSPB2 significantly reduced the extent of glomerular basement membranes thickening, mesangial expansion, and glomerular area as well. Mimecan protein expressions in diabetes mellitus were decreased approximately by 28% when compared with those in the control group (P < .05), and restored remarkably after GSPB2 treatment (P < .05). The expression of nuclear factor-κB (NF-κB) p65 in nuclear extracts, markedly higher in the diabetic mice than in the controls, was significantly suppressed by GSPB2. The findings of this study revealed that mimecan might become a new therapeutic target in the future and indicated that GSPB2 had beneficial effects not only on oxidative stress, but also on renal fibrosis, particularly in the diabetic kidney.

A flavonoid fraction purified from Rutaceae aurantiae (Daflon(R)) inhibiting AGE formation, reduces urinary albumin clearance and corrects hypoalbuminemia in normotensive and hypertensive diabetic rats.

AIM: Advanced glycation endproducts (AGEs) have been shown to contribute to alteration of glomerular permselectivity to proteins in diabetes. Oxidative stress is required for AGE formation. Therefore we studied the effect of an antioxidant micronized purified flavonoid fraction (MPFF, Daflon(R) 500 mg), on urinary albumin clearance in diabetic rats. METHODS: Hyperglycaemia was induced by streptozotocin 55 mg/kg IM at days 0 and 7 in normotensive Wistar rats (NWR, diabetes duration 5 months) or hypertensive Wistar Kyoto rats (SHR, diabetes duration 2 months). MPFF was administered at 300 mg/kg/day, from day -2 until sacrifice. RESULTS: After 5 months of diabetes in NWR, MPFF reduced albumin clearance from 729±92 to 392±60 nl/min/kg, p<0.01, and restored albuminemia from 20.4±0.9 to 24.0±1 g/l, p<0.05; albumin fractional clearance was significantly diminished in the flavonoid-treated diabetic rats (0.360±0.037‰ versus 1.335±0.430‰ in the diabetic controls, p<0.001); MPFF did not significantly modify blood glucose and plasma fructosamine levels. After 2 months of diabetes in SHR, MPFF reduced albumin clearance from 243±121 to 101±47 nl/min/kg, p<0.05, and restored albuminemia from 21.1±1.6 to 26.7±2.2 g/l (p<0.05); MPFF also decreased plasma fluorescence characteristic of AGEs (p<0.02). Besides hesperetin, a main metabolite of MPFF recovered in plasma, inhibited in vitro the formation of the crosslinking AGE pentosidine in collagen incubated with high glucose (p<0.001). CONCLUSION: Our results confirm the role of glycoxidative stress in diabetic nephropathy. MPFF might be useful as complementary treatment for preventing diabetic microangiopathy.

Impact of high glucose and transforming growth factor-ß on bioenergetic profiles in podocytes.

Diabetic nephropathy is the most common cause of chronic renal failure in industrialized countries. Depletion of podocytes plays an important role in the progression of diabetic glomerulopathy. Various factors in the diabetic milieu lead to serious podocyte stress driving the cells toward cell cycle arrest (p27(Kip1)), hypertrophy, detachment, and apoptosis. Mitochondria are responsible for oxidative phosphorylation and energy supply in podocytes. Recent studies indicated that mitochondrial dysfunction is a key factor in diabetic nephropathy. In the present study, we investigated metabolic profiles of podocytes under diabetic conditions. We examined oxygen consumption rates (OCRs) and oxidative phosphorylation complex activities in murine podocytes. Cells were exposed to high glucose for 48 hours, cultured for 10 passages under high-glucose conditions (30 mmol/L), or incubated with transforming growth factor-ß (5 ng/mL) for 24 hours. After prolonged exposure to high glucose, podocytes showed a significantly increased OCR at baseline and also a higher OCR after addition of oligomycin, indicating significant changes in mitochondrial energy metabolism. Higher OCRs after inhibition of respiration by rotenone also indicated changes in nonmitochondrial respiration. Podocytes stimulated with a proapoptotic concentration of transforming growth factor-ß displayed similar bioenergetic profiles, even with decreased citrate synthase activity. In all tested conditions, we found a higher cellular nicotinamide adenine dinucleotide content and changes in activities of respiratory chain complexes. In summary, we provide for the first time evidence that key factors of the diabetic milieu induce changes in glucose metabolism and mitochondrial function in podocytes.

Protective effects of Eucommia lignans against hypertensive renal injury by inhibiting expression of aldose reductase.

AIM OF THE STUDY: To investigate the protective effects and the underlying mechanism of Eucommia lignans against hypertensive renal injury. MATERIAL AND METHODS: Ten-week-old Wistar Kyoto rats and age matched spontaneously hypertension rats were used in the study. The SHR were randomly divided into 4 groups (n=7 for each group) and received different treatment for 16 weeks, which including saline, Captopril, Epalrestat and Eucommia lignans, respectively. System blood pressures of the rats were monitored once every 4 weeks. N-Acetyl-ß-D-glucosaminidase (NAG) activity and the ratio of albumin and urinary creatinine were chosen as the indices of kidney function. Then the structure and renal collagen type III expression of glomerular basement membrane were observed by microscopy and the renal aldose reductase (AR) expression was measured by immunohistochemistry. In vitro, the proliferation of mesangial cells induced by AngII was assayed by MTT, and the mRNA expression of AR was measured by RT-real-time PCR. RESULTS: The renal function, evaluated by NAG enzyme activity and the ratio of albumin to urinary creatinine, was significantly ameliorated by Eucommia lignans treatment. Meanwhile, Eucommia lignans decreased both the protein (P<0.05) and the mRNA expressed lever of AR (P<0.05). Eucommia lignans also decreased the high expression of collagen type III in SHR (P<0.05) and inhibited the proliferation of renal mesangial cells induced by AngII (P<0.05). CONCLUSION: Eucommia lignans have protective effects against hypertensive renal injury, and the protective effects may be partly due to inhibition of aldose reductase.

[Effects of Qufengtongluo recipe on proteinuria and glomerular filtration membrane in rats with adriamycin-induced nephropathy].

OBJECTIVE: To assess the therapeutic effect of Qufengtongluo (QFTL) recipe against proteinuria and glomerular filtration membrane damage in rats with adriamycin-induced nephropathy (AN). METHODS: Fifty-six SD rats were randomized into normal control (A) and AN model groups. In the AN model group, the rat AN models established by a single intravenous injection of adriamycin via the tail vein were subdivided into model (B), QFTL recipe (C), prednisone (D), and benazepril (E) groups 3 weeks after adriamycin injection. The 24-h urinary protein level was measured and the expression of anionic sites on the filtration membrane was evaluated using electron microscope with PEI staining. Nephrin expression on the glomerular filtration membrane was detected with indirect immunofluorescence assay. RESULTS: Compared with group A, the model group showed significantly increased level of 24-h urinary protein (P<0.01), suggesting successful establishment of the AN model. Treatment with QFTL recipe obviously lowered the 24-h urinary protein (P<0.01), and increased the expression of anionic sites and nephrin on the glomerular filtration membrane in the AN rats (P<0.01). CONCLUSION: QFTL recipe can effectively decrease 24-h urinary protein, improve the symptoms, and up-regulate the expressions of anionic sites and nephrin on the glomerular filtration membrane in rats with AN.

[Pentosan polysulfate sodium prevents kidney morphological changes and albuminuria in rats with type 1 diabetes]. / El pentosán polisulfato de sodio previene las alteraciones morfológicas renales y la albuminuria en ratas con diabetes tipo 1.

Decreased levels of glycosaminoglycans (GAGs) have been observed in the kidney and other organs, in human and animal models of diabetes. Long-term administration of heparins and other glycosaminoglycans has demonstrated a beneficial effect on morphological and functional kidney abnormalities in diabetic rats. We assessed the effect of pentosan polysulfate sodium (PPS), a semi-synthetic glycosaminoglycan with low anticoagulant activity, on kidney involvement in streptozotocin diabetic rats. Diabetes was induced in male Sprague-Dawley rats by i.v. administration of streptozotocin (STZ). Animals were randomly allocated to three groups: C = control, STZ and STZ + PPS = pretreated with PPS (15 mg/kg, s.c.). After three months of follow-up, blood and 24 h-urine samples were obtained, the animals were sacrificed and the kidney microdissected for morphometric analysis. Urinary albumin excretion was markedly increased in untreated diabetic rats (C = 0.26 ± 0.03 vs STZ = 7.75 ± 1.8 mg/24 h) and PPS treatment partially prevented the albumin rise (3.7 ± 0.7 mg/24 h), without affecting the metabolic control HbA1c (C = 3.6 ± 1.7; STZ = 8.82 ± 0.47; STZ + PPS = 8.63 ± 0.54). Electron microscope observation revealed typical renal lesions described in experimental diabetes (STZ group). PPS administration prevents the tubular basement membrane thickening and the loss of cytoarchitecture induced by experimental diabetes. Our data demonstrate that long-term administration of PPS has a favourable effect on morphological and functional abnormalities in kidneys of diabetic rats and suggests a potential therapeutic use for this compound.

Systematic review of the renal protective effect of Astragalus membranaceus (root) on diabetic nephropathy in animal models.

GOALS: Diabetic nephropathy (DN) has long been recognized as the leading cause of end-stage renal disease. Recent experimental studies have shown that Astragalus membranaceus (AM) (root) has an inhibitory effect on the oxidative stress that characterizes early DN. This systematic review assesses the efficacy and safety of AM (root), used as a single herb, in slowing the progression of DN in diabetic rat models. METHODS: We conducted both an electronic search and a search by hand of randomized, controlled AM (root) treatment studies (including its effective components) focusing on animal models of DN. Two reviewers independently selected and assessed the studies. RESULTS: Among the 41 articles identified, 13 reports that fulfilled the inclusion criteria were included. Significant beneficial effects were observed in the AM (root) treated groups compared to controls regarding fasting blood glucose levels (standardized mean difference [SMD]: -2.86, 95% confidential interval (CI): -4.26, -1.46, P < 0.001), glomerular filtration rate (SMD: -3.36, 95% CI: -4.69, -2.03, P < 0.00001), urinary albumin excretion rate (SMD: -2.46, 95% CI: -3.75, -1.16, P = 0.0002), and thickness of the glomerular basement membrane (SMD: -3.51, 95% CI: -6.68, -0.34, P = 0.03). CONCLUSIONS: AM (root) and its effective components are effective in reducing fasting blood glucose and albuminuria levels, in reversing the glomerular hyperfiltration state, and in ameliorating the pathological changes of early DN in rat models.