Diabetes-induced Renal Damage Research Articles

Similarities and differences between alpha-tocopherol and gamma-tocopherol in amelioration of inflammation, oxidative stress and pre-fibrosis in hyperglycemia induced acute kidney inflammation.

BACKGROUND/OBJECTIVESDiabetes mellitus (DM) is a major chronic disease which increases global health problems. Diabetes-induced renal damage is associated with inflammation and fibrosis. Alpha (AT) and gamma-tocopherols (GT) have shown antioxidant and anti-inflammatory effects in inflammation-mediated injuries. The primary aim of this study was to investigate effects of AT and GT supplementations on hyperglycemia induced acute kidney inflammation in alloxan induced diabetic mice with different levels of fasting blood glucose (FBG).MATERIALS/METHODSDiabetes was induced by injection of alloxan monohydrate (150 mg/kg, i.p) in ICR mice (5.5-week-old, male) and mice were subdivided according to their FBG levels and treated with different diets for 2 weeks; CON: non-diabetic mice, m-DMC: diabetic control mice with mild FBG levels (250 mg/dl ≤ FBG ≤ 450 mg/dl), m-AT: m-DM mice fed AT supplementation (35 mg/kg diet), m-GT: m-DM mice with GT supplementation (35 mg/kg diet), s-DMC: diabetic control mice with severe FBG levels (450 mg/dl < FBG), s-AT: s-DM mice with AT supplementation, s-GT: s-DM mice with GT supplementation.RESULTSBoth AT and GT supplementations showed similar beneficial effects on NFκB associated inflammatory response (phosphorylated inhibitory kappa B-α, interleukin-1β, C-reactive protein, monocyte chemotactic protein-1) and pre-fibrosis (tumor growth factor β-1 and protein kinase C-II) as well as an antioxidant emzyme, heme oxygenase-1 (HO-1) in diabetic mice. On the other hands, AT and GT showed different beneficial effects on kidney weight, FBG, and oxidative stress associated makers (malondialdehyde, glutathione peroxidase, and catalase) except HO-1. In particular, GT significantly preserved kidney weight in m-DM and improved FBG levels in s-DM and malondialdehyde and catalase in m- and s-DM, while AT significantly attenuated FBG levels in m-DM and improved glutathione peroxidase in m- and s-DM.CONCLUSIONSThe results suggest that AT and GT with similarities and differences would be considered as beneficial nutrients to modulate hyperglycemia induced acute renal inflammation. Further research with careful approach is needed to confirm beneficial effects of tocopherols in diabetes with different FBG levels for clinical applications.

Additive protection by LDR and FGF21 treatment against diabetic nephropathy in type 2 diabetes model

The onset of diabetic nephropathy (DN) is associated with both systemic and renal changes. Fibroblast growth factor (FGF)-21 prevents diabetic complications mainly by improving systemic metabolism. In addition, low-dose radiation (LDR) protects mice from DN directly by preventing renal oxidative stress and inflammation. In the present study, we tried to define whether the combination of FGF21 and LDR could further prevent DN by blocking its systemic and renal pathogeneses. To this end, type 2 diabetes was induced by feeding a high-fat diet for 12 wk followed by a single dose injection of streptozotocin. Diabetic mice were exposed to 50 mGy LDR every other day for 4 wk with and without 1.5 mg/kg FGF21 daily for 8 wk. The changes in systemic parameters, including blood glucose levels, lipid profiles, and insulin resistance, as well as renal pathology, were examined. Diabetic mice exhibited renal dysfunction and pathological abnormalities, all of which were prevented significantly by LDR and/or FGF21; the best effects were observed in the group that received the combination treatment. Our studies revealed that the additive renal protection conferred by the combined treatment against diabetes-induced renal fibrosis, inflammation, and oxidative damage was associated with the systemic improvement of hyperglycemia, hyperlipidemia, and insulin resistance. These results suggest that the combination treatment with LDR and FGF21 prevented DN more efficiently than did either treatment alone. The mechanism behind these protective effects could be attributed to the suppression of both systemic and renal pathways.

Renoprotection from Diabetic Complications in OVE Transgenic Mice by Endothelial Cell Specific Overexpression of Metallothionein

In an effort to test our working hypothesis that diabetes‐induced renal glomerular damage may be the result of oxidative insult, JTMT transgenic mice were produced that overexpress the antioxidant protein metallothionein specifically in endothelial cells. JTMT animals were crossed with severely diabetic OVE transgenic mice to determine whether an endothelial specific antioxidant transgene might provide renoprotection from chronic diabetic complications. In double transgenic 150 day‐old OVE‐JTMT mice, diabetic parameters including blood glucose and HbA1c were indistinguishable from age‐matched OVE mice. However, our data indicate that endothelial‐specific metallothionein overexpression in OVE‐JTMT mice reduced a number of nephropathic complications of diabetes including severe albuminuria. In addition, compared to OVE diabetic mice, double transgenic OVE‐JTMT animals showed significant protection to all major components of the glomerular filtration barrier (i.e. podocyte foot process effacement, glomerular basement membrane thickening, and endothelial damage as evidenced by reduced loss of percent area of glomerular luminal capillary endothelial fenestrations). Moreover, when compared to OVE diabetic animals, OVE‐JTMT mice showed reduced glomerular hypertrophy, lowered mesangial cell density and reduced total glomerular cytoproliferation. These results suggest a direct role of oxidative damage to endothelial cells and indicate that their targeted protection can reduce or delay several features of diabetic nephropathy.

Oligonol, a Low-Molecular-Weight Polyphenol Derived from Lychee Fruit, Attenuates Diabetes-Induced Renal Damage through the Advanced Glycation End Product–Related Pathway in db/db Mice

This study was conducted to examine whether oligonol, a low-molecular-weight polyphenol derived from lychee fruit, has an ameliorative effect on diabetes-induced alterations, such as advanced glycation end product (AGE) formation or apoptosis in the kidneys of db/db mice with type 2 diabetes. Oligonol [10 or 20 mg/(kg body weight · d), orally] was administered every day for 8 wk to prediabetic db/db mice, and its effect was compared with vehicle-treated db/db and normal control mice (m/m). The administration of oligonol decreased the elevated renal glucose concentrations and reactive oxygen species in db/db mice (P < 0.05). The increased serum urea nitrogen and creatinine concentrations, which reflect renal dysfunction in db/db mice, were substantially lowered by oligonol. Oligonol reduced renal protein expression of NAD(P)H oxidase subunits (p22 phagocytic oxidase and NAD(P)H oxidase-4), AGEs (except for pentosidine), and c-Jun N-terminal kinase B-targeting proinflammatory tumor necrosis factor-α (P < 0.05). Oligonol improved the expressions of antiapoptotic [B-cell lymphoma protein 2 (Bcl-2) and survivin] and proapoptotic [Bcl-2–associated X protein, cytochrome c, and caspase-3] proteins in the kidneys of db/db mice (P < 0.05). In conclusion, these results provide important evidence that oligonol exhibits a pleiotropic effect on AGE formation and apoptosis-related variables, representing renoprotective effects against the development of diabetic complications in db/db mice with type 2 diabetes.

Febuxostat Ameliorates Diabetic Renal Injury in a Streptozotocin-Induced Diabetic Rat Model

Background: Oxidative stress and inflammation are known to play central roles in the development of diabetic nephropathy (DN). Febuxostat is a novel non-purine xanthine oxidase (XO)-specific inhibitor developed to treat hyperuricemia. In this study, we investigated whether febuxostat could ameliorate DN via renoprotective mechanisms such as alleviation of oxidative stress and anti-inflammatory actions. Methods: Male Sprague-Dawley rats were divided into three groups: a normal group, a diabetes group (DM group), and a febuxostat-treated diabetes group (DM+Fx group). We administered 5 mg/kg of febuxostat to experimental rats for 7 weeks and evaluated clinical and biochemical parameters and XO and xanthine dehydrogenase (XDH) activity in hepatic tissue. The degree of oxidative stress and extent of inflammation were evaluated from urine samples and renal tissue collected from each group. Results: Diabetic rats (DM and DM+Fx groups) had higher blood glucose and kidney weight relative to body weight than normal rats. Albuminuria was significantly reduced in febuxostat-treated diabetic rats compared with untreated diabetic rats. Quantitative analysis showed that hepatic XO and XDH activities were higher in the DM groups, but decreased after treatment with febuxostat. Urinary 8-OHdG concentrations and renal cortical nitrotyrosine also indicated reduced oxidative stress in the DM+Fx group relative to the DM group. The number of ED-1-stained cells in the glomerulus and tubule of diabetic renal tissue decreased in febuxostat-treated diabetic rats relative to that of non-treated diabetic rats. Diabetic rats also expressed higher transcript levels of inflammatory genes (E-selectin and VCAM-1), an inflammation-induced enzyme (COX-2), and inflammatory mediators (ED-1 and NF-κB) than control rats; expression of these genes was significantly reduced by treatment with febuxostat. Conclusions: Febuxostat prevents diabetic renal injury such as albuminuria. This renoprotective effect appears to be due to attenuation of the inflammatory and oxidative effects of diabetes-induced renal damage through inhibition of XO and XDH activities.

Amelioration of streptozotocin-induced diabetic nephropathy by melatonin, quercetin, and resveratrol in rats.

The role of oxygen radicals are known for the pathogenesis of kidney damage. The aim of the present study was to investigate the antioxidative effects of melatonin, quercetin, and resveratrol on streptozotocin (STZ)-induced diabetic nephropathy in rats. A total of 35 male Wistar rats were divided into 5 groups as follows: control, diabetes mellitus (DM), DM + melatonin, DM + quercetin, and DM + resveratrol. All the injections started on the same day of single-dose STZ injection and continued for 30 days. At the end of this period, kidneys were removed and processed for routine histological procedures. Biochemical parameters and morphological changes were examined. In DM group, blood glucose levels were significantly increased, whereas body weights were decreased compared with the control group. Significant increases in blood urea nitrogen and tissue malondialdehyde (MDA) levels and decreases in superoxide dismutase and catalase activities were detected in DM group. Administration of melatonin, quercetin, and resveratrol significantly reduced these values. Melatonin was more efficient in reducing MDA levels than other antioxidants (p < 0.05). STZ-induced histopathological alterations including epithelial desquamation, swelling, intracytoplasmic vacuolization, brush border loss and peritubular infiltration. Additionally, basement membrane thickening and sclerotic changes were observed in glomerulus. Transforming growth factor-β1 positive cells were also increased. Melatonin, quercetin, and resveratrol significantly reduced these histopathological changes. Our results indicate that melatonin, quercetin, and resveratrol might be helpful in reducing diabetes-induced renal damage.

Multiple Low-Dose Radiation Prevents Type 2 Diabetes-Induced Renal Damage through Attenuation of Dyslipidemia and Insulin Resistance and Subsequent Renal Inflammation and Oxidative Stress

BackgroundDyslipidemia and lipotoxicity-induced insulin resistance, inflammation and oxidative stress are the key pathogeneses of renal damage in type 2 diabetes. Increasing evidence shows that whole-body low dose radiation (LDR) plays a critical role in attenuating insulin resistance, inflammation and oxidative stress.ObjectiveThe aims of the present study were to investigate whether LDR can prevent type 2 diabetes-induced renal damage and the underlying mechanisms.MethodsMice were fed with a high-fat diet (HFD, 40% of calories from fat) for 12 weeks to induce obesity followed by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg) to develop a type 2 diabetic mouse model. The mice were exposed to LDR at different doses (25, 50 and 75 mGy) for 4 or 8 weeks along with HFD treatment. At each time-point, the kidney weight, renal function, blood glucose level and insulin resistance were examined. The pathological changes, renal lipid profiles, inflammation, oxidative stress and fibrosis were also measured.ResultsHFD/STZ-induced type 2 diabetic mice exhibited severe pathological changes in the kidney and renal dysfunction. Exposure of the mice to LDR for 4 weeks, especially at 50 and 75 mGy, significantly improved lipid profiles, insulin sensitivity and protein kinase B activation, meanwhile, attenuated inflammation and oxidative stress in the diabetic kidney. The LDR-induced anti-oxidative effect was associated with up-regulation of renal nuclear factor E2-related factor-2 (Nrf-2) expression and function. However, the above beneficial effects were weakened once LDR treatment was extended to 8 weeks.ConclusionThese results suggest that LDR exposure significantly prevented type 2 diabetes-induced kidney injury characterized by renal dysfunction and pathological changes. The protective mechanisms of LDR are complicated but may be mainly attributed to the attenuation of dyslipidemia and the subsequent lipotoxicity-induced insulin resistance, inflammation and oxidative stress.

Low-dose radiation induces renal SOD1 expression and activity in type 1 diabetic mice

Purpose: Oxidative stress plays a critical role in the pathogenesis of diabetic nephropathy (DN). As an antioxidant, superoxide dismutase (SOD)-1 deficiency exacerbates but SOD1 supplementation prevents diabetes-induced renal damage. Previously, we have demonstrated that repetitive exposure to low-dose radiation (LDR) at 25 mGy significantly prevents DN. Whether this prevention is related to SOD1 expression and activity remains unknown. The aim of the present study was to explore the effects of different methods of LDR treatment on SOD1 expression and activity in the kidneys of diabetic mice.Materials and methods: C57BL/6J mice were induced with type 1 diabetes using streptozotocin (STZ). Diabetic mice were irradiated with whole-body X-rays at either a single dose of 25 mGy or 75 mGy, or three doses of 25 mGy and then sacrificed at different times. Body weight, blood glucose level, and renal SOD1 expression and activity were measured.Results: LDR had no impact on the body weights or blood glucose levels of the mice in either the normal or diabetic groups. A single exposure of LDR at 25 mGy did not preserve renal SOD1 expression and activity in diabetic mice, but a single exposure of LDR at 75 mGy or three exposures of LDR at 25 mGy could preserve them.Conclusion: The stimulation of renal SOD1 expression and activity by a single or cumulative LDR of 75 mGy may be one of the preventive mechanisms of DN observed in the previous study.

Resveratrol Ameliorates Diabetes-induced Renal Damage through Regulating the Expression of TGF-β1, Collagen IV and Th17/Treg-related Cytokines in Rats.

This study aimed at detecting the protective effects of resveratrol on diabetes-induced renal damage and on the expression of transforming growth factor-beta 1 (TGF-β1), collagen IV and Th17/Tregrelated cytokines in streptozotocin-induced diabetic rats. Twenty diabetic rats were further randomly divided into diabetic model group (DM group) and resveratrol group with 10 animals in each group. Another 1- non-diabetic rats served as control. The diabetic rats in the resveratrol group were administered resveratrol for eight consecutive weeks (via gavage, 50 mg/kg daily, dissolved in saline). Rats in the control group and DM group received the same volume of saline only (via gavage). Renal function was measured. Histopathology changes of the kidney tissue were observed using haematoxylin and eosin staining. Levels of TGF-β1 and collagen IV in kidney homogenate were measured with enzyme-linked immunosorbent assay (ELISA). The level of Th17-related cytokines (IL-17A, IL-25) and Treg-related cytokines (IL-35, IL-10) in serum and in the supernatant of the kidney homogenate were determined using ELISA. Diabetic rats had damaged renal function, higher levels of TGF-β1, collagen IV, IL-17A and IL-25, as well as lower levels of IL-35 and IL-10, when compared to the control rats. Compared to the diabetic rats without resveratrol treatment, application of resveratrol to the diabetic rats ameliorated the renal function, inhibited the expression of TGF-β1, collagen IV, IL-17A and IL-25, and increased the expression IL-35 and IL-10. Resveratrol might ameliorate diabetes-induced renal damage through mediating the balance of Th17/Treg-related cytokines and inhibiting the expression of TGF-β1 and collagen IV.

Attenuation of Hyperlipidemia- and Diabetes-Induced Early-Stage Apoptosis and Late-Stage Renal Dysfunction via Administration of Fibroblast Growth Factor-21 Is Associated with Suppression of Renal Inflammation

BackgroundLipotoxicity is a key feature of the pathogenesis of diabetic kidney disease, and is attributed to excessive lipid accumulation (hyperlipidemia). Increasing evidence suggests that fibroblast growth factor (FGF)21 has a crucial role in lipid metabolism under diabetic conditions.ObjectiveThe present study investigated whether FGF21 can prevent hyperlipidemia- or diabetes-induced renal damage, and if so, the possible mechanism.MethodsMice were injected with free fatty acids (FFAs, 10 mg/10 g body weight) or streptozotocin (150 mg/kg) to establish a lipotoxic model or type 1 diabetic model, respectively. Simultaneously the mice were treated with FGF21 (100 µg/kg) for 10 or 80 days. The kidney weight-to-tibia length ratio and renal function were assessed. Systematic and renal lipid levels were detected by ELISA and Oil Red O staining. Renal apoptosis was examined by TUNEL assay. Inflammation, oxidative stress, and fibrosis were assessed by Western blot.ResultsAcute FFA administration and chronic diabetes were associated with lower kidney-to-tibia length ratio, higher lipid levels, severe renal apoptosis and renal dysfunction. Obvious inflammation, oxidative stress and fibrosis also observed in the kidney of both mice models. Deletion of the fgf21 gene further enhanced the above pathological changes, which were significantly prevented by administration of exogenous FGF21.ConclusionThese results suggest that FFA administration and diabetes induced renal damage, which was further enhanced in FGF21 knock-out mice. Administration of FGF21 significantly prevented both FFA- and diabetes-induced renal damage partially by decreasing renal lipid accumulation and suppressing inflammation, oxidative stress, and fibrosis.

Protective effect of short-term genistein supplementation on the early stage in diabetes-induced renal damage.

Hyperglycemia-induced oxidative stress has been concerned in the development of diabetic nephropathy (DN), which may cause kidney damage associated with inflammation and fibrosis. This study has been conducted to investigate the role of genistein supplementation in an acute DN state. Mice with FBG levels more than 250 mg/dL after alloxan injection (single i.p., 150 mg/kg) were considered as diabetic. Diabetic mice (DM) were further subdivided according to their FBG levels, medium-high FBG (DMMH < 450 mg/dL) and high FBG (DMH; 450 mg/dL) and were administrated by an AIG-93G diet supplemented with different doses of genistein (0, 0.025 or 0.1%). After 2 weeks' treatment, the levels of kidney malondialdehyde (MDA), blood urea nitrogen (BUN), and plasma creatinine and lipid profiles, as well as oxidative stress and inflammation-related markers, were measured (P < 0.05). Genistein supplementation improved levels of FBG in the DMMH groups, but not in the DMH group, regardless of the treatment dose. Moreover, the supplementation attenuated kidney oxidative stress indicated by MDA, BUN, and plasma creatinine. In addition, genistein treatment decreased inflammatory markers such as nuclear factor kappa B (p65), phosphorylated inhibitory kappa B alpha, C-reactive protein, monocyte chemotactic protein-1, cyclooxygenase-2, and tumor necrosis factor-alpha and improved oxidative stress markers (nuclear-related factor E2, heme oxygenase-1, glutathione peroxidase, and superoxide dismutase isoforms) in treatment groups, regardless of the genistein treatment dose. Furthermore, genistein supplementation inhibited the fibrosis-related markers (protein kinase C, protein kinase C-beta II, and transforming growth factor-beta I) in the DN state. However, 0.1% genistein supplementation in diabetes with high FBG levels selectively showed a preventive effect on kidney damage. These results suggest that genistein might be a good protective substance for DN through regulation of oxidative stress and inflammation. In particular, genistein is more efficient in diabetes patients with medium-high blood glucose levels. Finally, it is required to establish the beneficial dosage of genistein according to blood glucose levels.

C-Peptide Reduces Mitochondrial Superoxide Generation by Restoring Complex I Activity in High Glucose-Exposed Renal Microvascular Endothelial Cells

Hyperglycemia-mediated microvascular damage has been proposed to originate from excessive generation of mitochondrial superoxide in endothelial cells and is the suggested mechanism by which the pathogenesis of diabetes-induced renal damage occurs. C-peptide has been shown to ameliorate diabetes-induced renal impairment. Yet, the mechanisms underlying this protective benefit remain unclear. The objective of this study was to determine whether C-peptide affords protection to renal microvascular endothelial cell mitochondria during hyperglycemia. Conditionally immortalized murine renal microvascular endothelial cells (MECs) were exposed to low (5.5 mM) or high glucose (25 mM) media with either C-peptide (6.6 nM) or its scrambled sequence control peptide for 24 or 48 hours. Respiratory control ratio, a measure of mitochondrial electrochemical coupling, was significantly higher in high glucose renal MECs treated with C-peptide than those of high glucose alone. C-peptide also restored high glucose-induced renal MEC mitochondrial membrane potential changes back to their basal low glucose state. Moreover, C-peptide prevented the excessive mitochondrial superoxide generation and concomitant reductions in mitochondrial complex I activity which are mediated by the exposure of the renal MECs to high glucose. Together, these data demonstrate that C-peptide protects against high glucose-induced generation of mitochondrial superoxide in renal MECs via restoration of basal mitochondrial function.

Effect of Oryeongsan on hypertonic stress‐induced water channel expression and apoptosis in renal collecting duct cells

Aquaporin‐2 (AQP2), a family of water channels, plays an important role in the urinary concentrating process and regulation of water balance in the kidney. Oryeongsan (ORS, Wulingsan) has been reported to possess renal protective effects from renal diseases such as diabetes‐induced renal damage, nephrocalcinosis. This study was conducted to evaluate the inhibitory effect of ORS on hypertonic stress‐induced AQP2 expression and apoptosis in inner medullary collecting duct cell lines (IMCD‐3). Hypertonic stress (175 mM NaCl) increased AQP2 expression, ORS attenuated the hypertonicity‐induced increase in protein and mRNA levels in a concentration‐dependent manner. Pretreatment with ORS attenuated hypertonicity‐induced cell death. Hypertonicity increased serum‐ and glucocorticoid‐inducible protein kinase (Sgk1) phosphorylation, however, ORS attenuated the hypertonicity‐induced Sgk1 activation. Tonicity‐responsive enhancer binding protein (TonEBP) mRNA was also recovered by ORS under hypertonic stress. Hypertonicity increased cAMP levels and the changes were blocked by ORS. On the other hand, hypertonic stress‐induced Bax or caspase‐3 expression was decreased by ORS, resulting in anti‐apoptotic effect. These results provided evidence that the beneficial effect of ORS in water balance and apoptosis against in vitro hypertonic stress of renal collecting ducts.

Low-Dose Radiation Activates Akt and Nrf2 in the Kidney of Diabetic Mice: A Potential Mechanism to Prevent Diabetic Nephropathy

Repetitive exposure of diabetic mice to low-dose radiation (LDR) at 25 mGy could significantly attenuate diabetes-induced renal inflammation, oxidative damage, remodeling, and dysfunction, for which, however, the underlying mechanism remained unknown. The present study explored the effects of LDR on the expression and function of Akt and Nrf2 in the kidney of diabetic mice. C57BL/6J mice were used to induce type 1 diabetes with multiple low-dose streptozotocin. Diabetic and age-matched control mice were irradiated with whole body X-rays at either single 25 mGy and 75 mGy or accumulated 75 mGy (25 mGy daily for 3 days) and then sacrificed at 1–12 h for examining renal Akt phosphorylation and Nrf2 expression and function. We found that 75 mGy of X-rays can stimulate Akt signaling pathway and upregulate Nrf2 expression and function in diabetic kidneys; single exposure of 25 mGy did not, but three exposures to 25 mGy of X-rays could offer a similar effect as single exposure to 75 mGy on the stimulation of Akt phosphorylation and the upregulation of Nrf2 expression and transcription function. These results suggest that single 75 mGy or multiple 25 mGy of X-rays can stimulate Akt phosphorylation and upregulate Nrf2 expression and function, which may explain the prevention of LDR against the diabetic nephropathy mentioned above.

Prevention of diabetic nephropathy by sulforaphane: possible role of Nrf2 upregulation and activation.

The present study was to investigate whether sulforaphane (SFN) can prevent diabetic nephropathy in type 1 diabetic mouse model induced by multiple low-dose streptozotocin. Diabetic and age-matched control mice were given SFN at 0.5 mg/kg body weight daily for 3 months. At the end of 3-month SFN treatment, the diabetic nephropathy, shown by renal inflammation, oxidative damage, fibrosis, and dysfunction, was significantly prevented along with an elevation of renal Nrf2 expression and transcription in diabetes/SFN group compared with diabetic group. However, this renal prevention by SFN was not seen when the 3-month SFN-treated diabetic mice were aged for additional 3 months without further SFN treatment. Nrf2-mediated renal protective effects in diabetes were evaluated in human renal tubular HK11 cells transfected with control and Nrf2 siRNA and treated with 27.5 mM mannitol or high glucose plus palmitate (300 μM). Blockade of Nrf2 expression completely abolished SFN prevention of the profibrotic effect induced by high glucose plus palmitate. These results support that renal Nrf2 expression and its transcription play important roles in SFN prevention of diabetes-induced renal damage. However, the SFN preventive effect on diabetes-induced renal pathogeneses is not sustained, suggesting the requirement of continual use of SFN for its sustained effect.

Beneficial effect of the leaves of Murraya koenigii (Linn.) Spreng (Rutaceae) on diabetes-induced renal damage in vivo

Murraya koenigii (Linn.) Spreng (curry leaf) is widely used as a nephroprotective agent in kidney's infirmities among diabetics by the traditional practitioners in Malaysia. However, the latter role of curry leaf has been grossly under reported and is yet to receive proper scientific evaluation. The present study was designed to investigate the beneficial effect of the leaves of Murraya koenigii (Linn.) on diabetes-induced renal damage in vivo with regard to prove its efficacy by local traditional practitioners in the treatment of kidney frailties in diabetics. Aqueous (AQ) extract of the leaves of Murraya koenigii (Linn.) was administered to both normal and streptozotocin (STZ) induced diabetic male rats (Sprague-Dawley strain). Animals were divided into six groups (n=6) and treated with variable dose levels of AQ extract (200 and 400mg/kg body weight/day) for 30 days. At the end of 30 days, animals were sacrificed, blood was collected, processed and stored at -70°C for the zestimation of serum urea and creatinine, changes in plasma antioxidant capacity by FRAP assay, and glutathione peroxidase levels, in the normal and STZ-induced diabetic rats. Histological changes of the kidneys of these animals were also evaluated by light microscopy to determine the beneficial effect of the leaves. Daily oral administration of variable dose levels of the AQ extract for 30 days, produced significant dose dependant decrease in serum urea and creatinine levels (p<0.001), and marked increase in the levels of plasma antioxidant capacity (p<0.01) in diabetic treated rats, compared to the control (non-diabetic) subjects. However, the normal treated rats showed minimal variation in these parameters in comparison to normal controls. Histological studies of the kidneys of these animals showed comparable tissue regeneration by the AQ extract. The results of our study scientifically support the traditional belief for using the leaves of Murraya koenigii (Linn.) as adjuvant, in the treatment of pain disorders related to renal impairments among diabetics.

Multicentric Validation of Proteomic Biomarkers in Urine Specific for Diabetic Nephropathy

BackgroundUrine proteome analysis is rapidly emerging as a tool for diagnosis and prognosis in disease states. For diagnosis of diabetic nephropathy (DN), urinary proteome analysis was successfully applied in a pilot study. The validity of the previously established proteomic biomarkers with respect to the diagnostic and prognostic potential was assessed on a separate set of patients recruited at three different European centers. In this case-control study of 148 Caucasian patients with diabetes mellitus type 2 and duration ≥5 years, cases of DN were defined as albuminuria >300 mg/d and diabetic retinopathy (n = 66). Controls were matched for gender and diabetes duration (n = 82).Methodology/Principal FindingsProteome analysis was performed blinded using high-resolution capillary electrophoresis coupled with mass spectrometry (CE-MS). Data were evaluated employing the previously developed model for DN. Upon unblinding, the model for DN showed 93.8% sensitivity and 91.4% specificity, with an AUC of 0.948 (95% CI 0.898-0.978). Of 65 previously identified peptides, 60 were significantly different between cases and controls of this study. In <10% of cases and controls classification by proteome analysis not entirely resulted in the expected clinical outcome. Analysis of patient's subsequent clinical course revealed later progression to DN in some of the false positive classified DN control patients.ConclusionsThese data provide the first independent confirmation that profiling of the urinary proteome by CE-MS can adequately identify subjects with DN, supporting the generalizability of this approach. The data further establish urinary collagen fragments as biomarkers for diabetes-induced renal damage that may serve as earlier and more specific biomarkers than the currently used urinary albumin.

The amelioration of streptozotocin diabetes-induced renal damage by Wu-Ling-San (Hoelen Five Herb Formula), a traditional Chinese prescription

Ethnopharmacological relevance Wu-Ling-San (Hoelen Five Herb Formula) is a Chinese prescription used to promote water metabolism. Aim of the study The present study was undertaken to characterize the effects of Wu-Ling-San on diabetic nephropathy. Materials and methods Streptozotocin (STZ)-diabetic rats were orally administrated with Wu-Ling-San (0.5, 1.5, 2.5 g/(kg day)) once a day for 10 weeks. Changes in the renal function related parameters in plasma and urine were analyzed at the end of 10-week administration. Kidney was isolated for pathology histology, immunohistochemistry staining and Western blot analyses. Results Wu-Ling-San (2.5 g/(kg day)) partially decreased the high plasma glucose level in diabetic rats. Diabetic-dependent alterations in urinary albumin, 24-h urinary albumin excretion rate, creatinine clearance, and glomerular mesangial matrix expansion were ameliorated by Wu-Ling-San. The increased expression of nuclear factor-kB as well as transforming growth factor-β 1 and the progressive accumulation of fibronectin in kidney of diabetic rats were attenuated by Wu-Ling-San. Not only the elevated levels of advanced glycation end products (AGEs) and mitochondrial thiobarbituric acid-reactive substance, but also the higher levels of N ɛ-(carboxymethyl)lysine and receptor for AGEs in kidney of diabetic rats were ameliorated by Wu-Ling-San. Conclusions : Wu-Ling-San posses an anti-diabetic property with plasma glucose lowering action accompanied with amelioration of glycation-mediated renal damage.

Zinc supplementation partially prevents renal pathological changes in diabetic rats

We have demonstrated that Zn supplementation mediated up-regulation of cardiac metallothionein (MT) as a potent antioxidant prevented the development of diabetic cardiomyopathy. The present study was undertaken to test whether induction of renal MT synthesis by Zn supplementation protects the kidney from diabetes-induced damage. Streptozotocin-induced diabetic rats were treated with and without Zn supplementation at 5 mg/kg in drinking water for 3 months. Diabetic renal damage was detected by examining renal pathological alterations and 24-h urinary protein levels. Three-month Zn supplementation immediately after the onset of diabetes, partially but significantly, prevented the kidney from diabetes-induced increases in 24-h urinary proteins and pathological alterations. Diabetes-induced renal oxidative damage, inflammation and up-regulated expression of profibrosis mediator connective tissue growth factor (CTGF) were also markedly attenuated by Zn supplementation, along with significant increases in Zn levels concomitant with MT expression in renal tubular cells. Direct exposure of renal tubular (HK11) cells to high levels of glucose (HG) induced CTGF up-regulation predominantly through ERK (extracellular signal-regulated kinase)1/2-dependent, and partially through p38 mitogen-activated protein kinase (MAPK)-dependent pathways. Pretreatment of HK11 cells with Zn or cadmium induced MT expression and also significantly suppressed HG-induced CTGF expression. These results provide the first evidence for Zn supplementation to attenuate diabetes-induced renal pathological changes, likely through prevention of hyperglycemia-induced CTGF expression by Zn-induced MT in renal tubular cells.

Rosaglitazone (RGZ) decreases renal damage in spontaneously diabetic Goto‐Kakizaki (GK) rats

Rosiglitazone (RGZ) is a member of a class of oral antidiabetic agents that increase insulin sensitivity and improve glucose tolerance. It was reported that in patients with type II diabetes and nephropathy RGZ also decreased blood pressure and albuminuria. We hypothesized that administration of RGZ to spontaneously type II diabetic GK rats would decrease diabetes-induced renal damage by inhibiting the inflammatory component. Twelve week old male GK rats were treated for four weeks with RGZ (n=4, 10mg/kg). RGZ treatment did not alter plasma insulin levels, but significantly decreased blood glucose levels after two weeks of treatment (150 ± 8 and 115 ± 2 mg/dL for vehicle and RGZ treated groups, P<0.05). Urinary albumin excretion, a marker of renal damage, decreased from 1.6 ± 0.4 mg/day in control animals to 0.7 ± 0.1 mg/day in the RGZ treated group (P<0.05). Monocyte chemoattractant protein-1 excretion, a marker of inflammation, was also decreased with RGZ treatment (7.8 ± 1.0 and 5.2 ± 0.5 pg/day for vehicle and RGZ treated groups, P<0.05). RGZ treatment did not alter cortical COX-1 protein levels, but decreased inducible COX-2 protein levels by 32%. This was accompanied by a 38% decrease in urinary PGE2 excretion. Together, these data support the hypothesis that RGZ treatment decreases renal damage in an animal model of type II diabetes by decreasing the inflammatory component and reducing COX-2 protein and metabolites.