Amelioration Of Diabetic Nephropathy Research Articles

Amelioration of diabetic nephropathy in mice by a single intravenous injection of human mesenchymal stromal cells at early and later disease stages is associated with restoration of autophagy

Background and aimsMesenchymal stromal cells (MSCs) a potentially effective disease-modulating therapy for diabetic nephropathy (DN) but their clinical translation has been hampered by incomplete understanding of the optimal timing of administration and in vivo mechanisms of action. This study aimed to elucidate the reno-protective potency and associated mechanisms of single intravenous injections of human umbilical cord-derived MSCs (hUC-MSCs) following shorter and longer durations of diabetes.MethodsA streptozotocin (STZ)-induced model of diabetes and DN was established in C57BL/6 mice. In groups of diabetic animals, human (h)UC-MSCs or vehicle were injected intravenously at 8 or 16 weeks after STZ along with vehicle-injected non-diabetic animals. Diabetes-related kidney abnormalities was analyzed 2 weeks later by urine and serum biochemical assays, histology, transmission electron microscopy and immunohistochemistry. Serum concentrations of pro-inflammatory and pro-fibrotic cytokines were quantified by ELISA. The expression of autophagy-related proteins within the renal cortices was investigated by immunoblotting. Bio-distribution of hUC-MSCs in kidney and other organs was evaluated in diabetic mice by injection of fluorescent-labelled cells.ResultsCompared to non-diabetic controls, diabetic mice had increases in urine albumin creatinine ratio (uACR), mesangial matrix deposition, podocyte foot process effacement, glomerular basement membrane thickening and interstitial fibrosis as well as reduced podocyte numbers at both 10 and 18 weeks after STZ. Early (8 weeks) hUC-MSC injection was associated with reduced uACR and improvements in multiple glomerular and renal interstitial abnormalities as well as reduced serum IL-6, TNF-α, and TGF-β1 compared to vehicle-injected animals. Later (16 weeks) hUC-MSC injection also resulted in reduction of diabetes-associated renal abnormalities and serum TGF-β1 but not of serum IL-6 and TNF-α. At both time-points, the kidneys of vehicle-injected diabetic mice had higher ratio of p-mTOR to mTOR, increased abundance of p62, lower abundance of ULK1 and Atg12, and reduced ratio of LC3B to LC3A compared to non-diabetic animals, consistent with diabetes-associated suppression of autophagy. These changes were largely reversed in the kidneys of hUC-MSC-injected mice. In contrast, neither early nor later hUC-MSC injection had effects on blood glucose and body weight of diabetic animals. Small numbers of CM-Dil-labeled hUC-MSCs remained detectable in kidneys, lungs and liver of diabetic mice at 14 days after intravenous injection.ConclusionsSingle intravenous injections of hUC-MSCs ameliorated glomerular abnormalities and interstitial fibrosis in a mouse model of STZ-induced diabetes without affecting hyperglycemia, whether administered at relatively short or longer duration of diabetes. At both time-points, the reno-protective effects of hUC-MSCs were associated with reduced circulating TGF-β1 and restoration of intra-renal autophagy.Graphical abstract

The Role of Diacylglycerol Kinase in the Amelioration of Diabetic Nephropathy.

The drastic increase in the number of patients with diabetes and its complications is a global issue. Diabetic nephropathy, the leading cause of chronic kidney disease, significantly affects patients’ quality of life and medical expenses. Furthermore, there are limited drugs for treating diabetic nephropathy patients. Impaired lipid signaling, especially abnormal protein kinase C (PKC) activation by de novo-synthesized diacylglycerol (DG) under high blood glucose, is one of the causes of diabetic nephropathy. DG kinase (DGK) is an enzyme that phosphorylates DG and generates phosphatidic acid, i.e., DGK can inhibit PKC activation under diabetic conditions. Indeed, it has been proven that DGK activation ameliorates diabetic nephropathy. In this review, we summarize the involvement of PKC and DGK in diabetic nephropathy as therapeutic targets, and its mechanisms, by referring to our recent study.

Casticin Alleviates the Proliferation and Extracellular Matrix Deposition in Glomerular Mesangial Cells Induced by High Levels of Glucose

Diabetic nephropathy is a common complication of diabetes associated with defects in the extracellular matrix. However, its precise mechanism remains to be explored. Casticin (3′, 5-dihydroxy-3, 4′, 6, 7-tetramethoxyl flavone) is a bioactive component of Fructus vitexis known to exhibit many biological and pharmacological effects. Herein, we have explored the role and mechanism of casticin-mediated amelioration of diabetic nephropathy. Using a high glucose induced glomerular mesangial cell model, we report casticin inhibition of high glucose induced excessive glomerular mesangial cell proliferation, inflammation, and extracellular matrix deposition. Casticin suppressed TGF-β1/Smad pathway, and therefore alleviated the proliferation and extracellular matrix deposition of glomerular mesangial cells. These data suggest that casticin could serve as a promising drug for the management of diabetic nephropathy.

Amelioration of Diabetic Nephropathy by Targeting Autophagy via Rapamycin or Fasting: Relation to Cell Apoptosis/Survival.

Autophagy has been demonstrated to have a beneficial effect on diabetic nephropathy (DN). Rapamycin, an inhibitor of mTOR, was shown to stimulate β-cell autophagy. However, its effects on preventing or ameliorating DN is unclear, and its effects are worth studying. As fasting is now an attractive protective strategy, we aim to compare its effect to rapamycin effects on pancreatic and renal cells. Twenty-eight adult male Wistar Albino rats were randomly divided into four groups, using streptozotocin (STZ) to induce diabetes mellitus (DM). Autophagy was induced by two ways; rapamycin or fasting. The extent of autophagy and apoptosis were investigated by measuring the level of LC3B and p53 proteins, respectively, in pancreatic and kidney tissues using Western blotting (WB) technique and imaging the renal cells under transmission electron microscope. The efflux transporter P-glycoprotein was quantified by WB as well. Rapamycin-induced autophagy occurred concurrently with apoptosis. On the other hand, fasting supported P-glycoprotein recovery and renal cell survival together with disabling β-cells apoptosis. In conclusion, this study provides a potential link between rapamycin or fasting for the cross-regulation of apoptosis and autophagy in the setting of cell stress as DN. Unlike rapamycin, fasting enhanced the active expression of ABCB1 efflux protein, providing insights on the potential ameliorative effects of fasting in DN that require further elucidation.

Amelioration of diabetic nephropathy with extracts of Pterocarpus santalinus heart wood and Brassica nigra seeds via regulation of insulin resistance and modulation of genes in streptozotocin induced diabetic rats

The current study was designed to investigate the possible effects of aqueous extract of Pterocarpus santalinus heart wood and Brassica nigra seeds on streptozotocin (STZ) induced diabetic rats. Adult male albino rats of 24 numbers were used in this study and were divided into four groups, each group contain 6 animals. For induction of diabetes rats were received STZ (65 mg/kg body weight). After STZ induction the remaining three groups were split as follow: group 2 served as diabetic untreated group, group 3 served as diabetic group treated with aqueous Pterocarpus santalinus extract and group 4 served as diabetic group treated with aqueous Brassica nigra extract. STZ administration produced significant increase in serum glucose, HbA1c, Homeostatic Model Assessment insulin resistance (HOMA-IR), lipids, creatinine and urea levels; also, significant decrease in insulin level, Homeostatic Model Assessment insulin sensitivity (HOMA-IS), Quantitative Insulin Sensitivity Check Index (QUICKI) and Glomerular filtration rate (GFR). At molecular level, STZ administration produced significant up-regulation in the mRNA of Thioredoxin-interacting protein (TXNIP), The Nod-like receptor protein 3(NLRP3) and inflammasome and Apoptosis-enhancing nuclease (AEN). The effects of aqueous extracts of P. santalinus wood and B. nigra seeds were evidenced by significant decreased in serum levels of glucose, HbA1c, lipids, creatinine and urea as well as significant increase in insulin, HDL and GFR level. Further treatment with aqueous extracts of Pterocarpus santalinus and Brassica nigra down-regulated the mRNA of TXNIP, NLRP3 and AEN. The results of this study concluded that aqueous extracts of P. santalinus and B. nigra reduced the effects of STZ- induced diabetes and they can be used for the treatment of diabetes and its complication.

Amelioration of Diabetic Nephropathy in Streptozotocin-Induced Diabetic Rats by Acacia catechu Leaves Extract

Abstract Objective The present study was performed to evaluate the ethanolic extract of leaves of Acacia catechu (A. catechu) for its effect on streptozotocin (STZ)-induced diabetes mellitus (DM) and its renal complications in male Wistar albino rats. Materials and Methods Male Wistar albino rats were grouped into control (A), STZ-induced DM (B), STZ-induced DM rats with A. catechu orally of 75 mg/kg body weight (kbw) for 35 days (C), with each group having six rats (n = 6) weighing between 200 to 250 g each. Group A receives only water, orally; group B receives a single dose of STZ at 45 mg/kbw intraperitoneal administration (IP); group C receives STZ IP and oral A. catechu for 35 days. On the 36th day, animals were euthanized, the kidney tissues were analyzed for biochemical parameters, such as GOT (glutamic oxaloacetic transaminase), GPT (glutamic pyruvic transaminase), oxidative stress assessment parameters, and histopathological studies. Results In group C rats, activities of the enzymes were nearer to group A when compared with group B. Histopathological findings were also suggesting that renal toxicity were observed at a lesser extent in group C. Conclusion The ethanolic extract of A. catechu signified as nephroprotective effect. The present data could provide adequate confirmation of the efficacy of ethanolic extract of leaves of A. catechu for further experimental studies on a standardized formulation.

Amelioration of Diabetic Nephropathy Using a Retinoic Acid Receptor β2 Agonist

Vitamin A (VA) and its derivatives, known as retinoids, play critical roles in renal development through retinoic acid receptor β2 (RARβ2). Disruptions in VA signaling pathways are associated with the onset of diabetic nephropathy (DN). Despite the known role of RARβ2 in renal development, the effects of selective agonists for RARβ2 in a high fat diet (HFD) model of DN are unknown. Here we examined whether AC261066 (AC261), a highly selective agonist for RARβ2, exhibited therapeutic effects in a HFD model of DN in C57BL/6 mice. Twelve weeks of AC261 administration to HFD mice was well tolerated, with no observable side effects. Compared to HFD mice, HFD + AC261 treated mice had improved glycemic control and reductions in proteinuria and urine albumin to creatinine ratio. A number of molecular hallmarks of DN were mitigated in HFD + AC261 treated mice, including reductions in tubule lipid droplets (LDs), podocyte (POD) effacement, endothelial cell (EC) collapse, mesangial expansion, and glomerular basement membrane (GBM) thickening., Mesangial and tubule interstitial expression of the myofibroblast markers α‐smooth muscle actin (α‐SMA) and type IV collagen (Col‐IV) was lower in HFD + AC261 treated mice compared to HFD alone. Ultrastructural and immunohistochemistry analyses showed that, compared to HFD mice, HFD + AC261 treated mice showed preservation of POD foot process and slit diaphragm morphology, and an increase in the levels of slit‐diagram protein podocin and the transcription factor WT1 in PODs. Given the need for novel DN therapies, our results warrant further studies of the therapeutic properties of AC261 in DN.Support or Funding InformationThis research was supported in part by Weill Cornell funds and by NIH R01DK113088 to LJG. SET was supported by the National Institutes of Health (T32 CA062948)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Amelioration of diabetic nephropathy by SGLT2 inhibitors independent of its glucose-lowering effect: A possible role of SGLT2 in mesangial cells

Several clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on diabetic nephropathy. The underlying mechanisms are not fully understood. We found that administration of canagliflozin at a low dose (0.01 mg/kg/day) did not affect either blood glucose levels or glycosuria, but it improved albuminuria and mesangial expansion in db/db mice to a similar extent as at a high dose (3.0 mg/kg/day) that lowered blood glucose levels. This indicated the existence of a tubular SGLT2-independent reno-protective mechanism. Here we focused on the potential role of SGLT2 in mesangial cells (MCs). Western blot analysis revealed the expression of SGLT2 in cultured mouse MCs. Exposure of MCs to high glucose levels for 72 h significantly increased the expression of SGLT2. Canagliflozin or ipragliflozin (both 100 nM) treatment inhibited glucose consumption in the medium under high-glucose conditions but not under normal-glucose conditions. Furthermore, canagliflozin inhibited high-glucose-induced activation of the protein kinase C (PKC)-NAD(P)H oxidase pathway and increases in reactive oxygen species (ROS) production. Thus, the inhibition of mesangial SGLT2 may cause an inhibition of PKC activation and ROS overproduction in diabetic nephropathy, and this may at least in part account for the reno-protective effect of SGLT2 inhibitors.

Amelioration of diabetic nephropathy using pomegranate peel extract-stabilized gold nanoparticles: assessment of NF-κB and Nrf2 signaling system.

BackgroundDiabetic nephropathy (DN), an end-stage renal disorder, has posed a menace to humankind globally, because of its complex nature and poorly understandable intricate mechanism. In recent times, functional foods as potential health benefits have been gaining attention of consumers and researchers alike. Rich in antioxidants, the peel and seed of pomegranate have previously demonstrated protection against oxidative-stress-related diseases, including cardiovascular disorders, diabetes, and cancer.PurposeThis study was designed to investigate the ameliorative role of pomegranate peel extract–stabilized gold nanoparticle (PPE-AuNP) on streptozotocin (STZ)-induced DN in an experimental murine model.MethodsFollowing the reduction methods, AuNP was prepared using the pomegranate peel ellagitannins and characterized by particle size, physical appearance, and morphological architecture. Modulatory potential of PPE-AuNP was examined through the plethora of biochemical and high throughput techniques, flow cytometry, immunoblotting, and immunofluorescence.ResultsThe animals treated with PPE-AuNP markedly reduced the fasting blood glucose, renal toxicity indices, and serum TC and TG in a hyperglycemic condition. As evident from an increased level of plasma insulin level, PPE-AuNP normalized the STZ-induced pancreatic β-cell dysfunction. The STZ-mediated suppression of endogenous antioxidant response was restored by the PPE-AuNP treatment, which reduced the generation of LPO as well as iROS. Furthermore, the hyperglycemia-mediated augmentation of protein glycation, followed by the NOX4/p-47phox activation, diminished with the application of PPE-AuNP. The histological and immunohistochemical findings showed the protective efficacy of PPE-AuNP in reducing STZ-induced glomerular sclerosis and renal fibrosis. In addition, it reduced proinflammatory burden through the modulation of the MAPK/NF-κB/STAT3/cytokine axis. Simultaneously, PI3K/AKT-guided Nrf2 activation was evident upon the PPE-AuNP application, which enhanced the antioxidant response and maintained hyperglycemic homeostasis.ConclusionThe findings indicate that the use of PPE-AuNPs might act as an economic therapeutic remedy for alleviating DN.

Amelioration of diabetic nephropathy in db/db mice treated with tibetan medicine formula Siwei Jianghuang Decoction Powder extract

Siwei Jianghuang Decoction Powder (SWJH) documented originally in the Four Medical Tantras-Blue Glaze exhibited beneficial effects on diabetic nephropathy (DN) via combined synergistically action of multiple formula components including Curcumae longae Rhizoma, Berberidis dictyophyllae Cortex, Phyllanthi Fructus and Tribuli Fructus. This study investigated the effects of SWJH on DN in db/db mice and possible underlying mechanisms. The ten weeks old db/db mice treated with SWJH by intra-gastric administration once a day for 8 weeks. After 8 weeks, body weight, water and food intake of mice were recorded. The level of fasting blood glucose (FBG) was measured. Serum creatinine (Scr), blood urea nitrogen (BUN), urine microalbumin (UMAlb), serum uric acid (UA) and urinary albumin excretion (UAE) were detected. An enzyme-linked immunosorbent assay was performed to test serum vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1). Real-time PCR and Western blot analysis were used to test mRNA and protein expression of hypoxia inducible factor-1α (HIF-1α), VEGF and TGF-β1 in kidney tissue. SWJH treatment significantly reduced the levels of FBG, Scr, BUN, UMAlb, UA and UAE and retarded renal fibrosis. SWJH treatment further significantly reduced serum TGF-β1 level and downregulated the expression of HIF-1α, VEGF and TGF-β1 at both mRNA and protein levels. Principal component analysis and partial least squares regression and hierarchical cluster analysis demonstrated that SWJH treatment significantly ameliorated renal damage in DN mice. These consequences suggested that SWJH formulations were effective in the treatment of DN through regulating the HIF-1α, VEGF and TGF-β1 overexpression.

Amelioration of diabetic nephropathy by oral administration of d-α-tocopherol and its mechanisms.

Diabetic nephropathy (DN) is a diabetic vascular complication, and abnormal protein kinase C (PKC) activation from increased diacylglycerol (DG) production in diabetic hyperglycemia is one of the causes of DN. Diacylglycerol kinase (DGK) converts DG into phosphatidic acid. In other words, DGK can attenuate PKC activity by reducing the amount of DG. Recently, we reported that intraperitoneally administered d-α-tocopherol (vitamin E, αToc) induces an amelioration of DN in vivo through the activation of DGKα and the prevention of podocyte loss. However, the effect of the oral administration of αToc on DN in mice remains unknown. Here, we evaluated the effect of oral administration of αToc on DN and its molecular mechanism using streptozocin-induced diabetic mice. Consequently, the oral administration of αToc significantly ameliorated the symptoms of DN by preventing the loss of podocytes, and it was revealed that the inhibition of PKCactivity was involved in this amelioration.

Epidermal growth factor receptor signaling and the progression of diabetic nephropathy.

Epidermal growth factor receptor signaling and the progression of diabetic nephropathy.

Amelioration of diabetic nephropathy by orange peel extract in rats

This study was aimed to evaluate the effect of alcoholic orange peel extract (OPE) on streptozotocin-induced diabetic nephropathy. Four weeks after the induction of diabetes, treatment with OPE (100 and 200 mg/kg) was further given for 4 weeks. Treatment with OPE 200 improved renal functions and significantly prevented the increase in creatinine, urea and blood urea nitrogen levels. Histological analysis of the kidneys revealed that tubulointerstitial fibrosis index was significantly decreased in OPE 200-treated group. The results indicated the prevention of diabetic nephropathy in rats by OPE treatment and suggest OPE as a potential treatment option.

Dual therapy of rosiglitazone/pioglitazone with glimepiride on diabetic nephropathy in experimentally induced type 2 diabetes rats

Diabetic nephropathy is a major cause of end-stage renal disease (ESRD) in the general population. It is estimated that diabetic nephropathy will eventually develop in about 40% of all patients with diabetes; therefore, prevention is critical for delaying the development and progression of diabetic kidney disease. Despite extensive efforts, medical advances are still not successful enough to prevent the progression of the disease. In the present study, we focused on the comparison of combination therapies and whether they offered additional renopro-tection. Type 2 diabetes mellitus was induced by intraperitoneally administering streptozotocin (90 mg/kg) in neonatal rats and then these rats were treated with rosiglitazone (1.0 mg/kg) in combination with glimepiride (0.5 mg/kg) or with pioglitazone (2.5 mg/kg) in combination with glimepiride (0.5 mg/kg). Diabetic nephropathy markers were evaluated by biochemical and ELISA kits and renal structural changes were examined by light mi-croscopy and transmission electron microscopy. Results show that the combination of pioglitazone with glimepir-ide is more effective in amelioration of diabetic nephropathy than rosiglitazone with glimepiride drug therapy due to glycemic control, suppressing albumin excretion rate, total protein excretion rate and augmented TNF-a signaling during the development of streptozotocin induced type 2 diabetic nephropathy.

When to initiate ACEI/ARB therapy in patients with type 1 and 2 diabetes

Angiotensin converting enzyme inhibitors (ACEI) and angiotensin 2 receptor blockers (ARB) have become a mainstay of adjunctive therapy for the prevention and amelioration of diabetic nephropathy. Although ACEI were shown over 20 years ago to slow the rate of loss of renal function in diabetic subjects with decreased renal function, the question of how early in the course of diabetes to introduce them remains unresolved. Recent studies suggest that very early initiation of ACEI/ARB therapy may not have demonstrable beneficial effects even over a period of years.

Long-Term Treatment of Sirolimus but Not Cyclosporine Ameliorates Diabetic Nephropathy in the Rat

Not just de novo induction of diabetes mellitus, but also the progression of diabetic nephropathy may be enhanced under immunosuppressive therapy after organ transplantation. We evaluated whether sirolimus (SRL) or cyclosporine A (CsA) therapy would be a superior immunosuppressant in streptozotocin-induced diabetic nephropathy. Diabetes was induced by intravenous injection of streptozotozin (60 mg/kg body weight) in 26 male Sprague-Dawley rats. Eight days after diabetes induction, animals were divided into three groups, which were treated with placebo (n=8), SRL (n=9), or CsA (n=9). Six nondiabetic placebo-treated rats were included as controls. After 19 weeks of diabetes, SRL significantly decreased fibrosis as assessed by periodic acid Schiff staining and by specific extracellular matrix proteins such as fibronectin and laminin at messenger RNA and protein level compared with the diabetic placebo group. SRL ameliorated renal inflammation, glomerular hypertrophy, and podocyte loss as indicated by morphometric and immunohistological analysis. SRL lowered expression and activity of glomerular transforming growth factor-beta1/2 and vascular endothelial growth factor, all of which are considered central cytokines in the pathogenesis of diabetic nephropathy. In contrast, calcineurin phosphatase inhibition through CsA did not ameliorate any of the features of diabetic nephropathy compared with placebo treatment but slightly aggravated glomerular fibrosis without affecting transforming growth factor-beta1/2 or vascular endothelial growth factor. Compared with CsA, SRL by anti-inflammatory, antifibrotic, and podocyte-protective effects clearly seems to be the superior treatment of prevention or amelioration of diabetic nephropathy in the rat.

Cellular and physiological effects of C-peptide

In recent years, accumulating evidence indicates a biological function for proinsulin C-peptide. These results challenge the traditional view that C-peptide is essentially inert and only useful as a surrogate marker of insulin release. Accordingly, it is now clear that C-peptide binds with high affinity to cell membranes, probably to a pertussis-toxin-sensitive G-protein-coupled receptor. Subsequently, multiple signalling pathways are potently and dose-dependently activated in multiple cell types by C-peptide with the resulting activation of gene transcription and altered cell phenotype. In diabetic animals and Type 1 diabetic patients, short-term studies indicate that C-peptide also enhances glucose disposal and metabolic control. Furthermore, results derived from animal models and clinical studies in Type 1 diabetic patients suggest a salutary effect of C-peptide in the prevention and amelioration of diabetic nephropathy and neuropathy. Therefore a picture of Type 1 diabetes as a dual-hormone-deficiency disease is developing, suggesting that the replacement of C-peptide alongside insulin should be considered in its management.

Rosiglitazone reduces renal and plasma markers of oxidative injury and reverses urinary metabolite abnormalities in the amelioration of diabetic nephropathy

Recent studies suggest that thiazolidinediones ameliorate diabetic nephropathy (DN) independently of their effect on hyperglycemia. In the current study, we confirm and extend these findings by showing that rosiglitazone treatment prevented the development of DN and reversed multiple markers of oxidative injury in DBA/2J mice made diabetic by low-dose streptozotocin. These diabetic mice developed a 14.2-fold increase in albuminuria and a 53% expansion of renal glomerular extracellular matrix after 12 wk of diabetes. These changes were largely abrogated by administration of rosiglitazone beginning 2 wk after the completion of streptozotocin injections. Rosiglitazone had no effect on glycemic control. Rosiglitazone had similar effects on insulin-treated diabetic mice after 24 wk of diabetes. Podocyte loss and glomerular fibronectin accumulation, other markers of early DN, were prevented by rosiglitazone in both 12- and 24-wk diabetic models. Surprisingly, glomerular GLUT1 levels did not increase and nephrin levels did not decrease in the diabetic animals; neither changed with rosiglitazone. Plasma and kidney markers of protein oxidation and lipid peroxidation were significantly elevated in the 24-wk diabetic animals despite insulin treatment and were reduced to near-normal levels by rosiglitazone. Finally, urinary metabolites were markedly altered by diabetes. Of 1,988 metabolite features identified by electrospray ionization time of flight mass spectrometry, levels of 56 were altered more than twofold in the urine of diabetic mice. Of these, 21 were returned to normal by rosiglitazone. Thus rosiglitazone has direct effects on the renal glomerulus to reduce reactive oxygen species accumulation to prevent type 1 diabetic mice from development of DN.

Effects of N-hexacosanol on nitric oxide synthase system in diabetic rat nephropathy

We attempted to clarify the effects of cyclohexenonic long-chain fatty alcohol (N-hexacosanol) on nitric oxide synthase (NOS) in streptozotocin-induced diabetic nephropathy. After induction of experimental diabetes with streptozotocin, rats were maintained for 8 weeks with or without treatment by N-hexacosanol (8 mg/kg i.p. every day). Urinary albumin excretion, blood chemistry, immunoblot analysis, and real-time polymerase chain reactions (real-time PCR) of endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS) were investigated. Although N-hexacosanol had no effects on serum glucose or insulin level, it normalized serum creatinine and urinary albumin excretion. N-hexacosanol was found to improve the diabetes-induced alterations in the eNOS, iNOS, and nNOS protein and their mRNA levels. Histologically, N-hexacosanol inhibited the progression to glomerular sclerosis. Our data suggest that N-hexacosanol improves diabetes-induced NOS alterations in the kidney, resulting in the amelioration of diabetic nephropathy.

P40: Amelioration of diabetic nephropathy after gastric bypass surgery

P40: Amelioration of diabetic nephropathy after gastric bypass surgery