Diabetic Renal Damage Research Articles

Enhanced Hydrogen Peroxide and renin release in Primary cultures of Juxtaglomerular (JG) cells from diabetic mice

Diabetes mellitus and its complications represent an increasing burden for healthcare. A large fraction of patients with diabetes mellitus develops diabetic nephropathy. The Akita mice strain is one of the few mouse models of diabetes mellitus that shows features of the human disease including hypertension and kidney damage. Previous reports have shown increased levels of reactive oxygen species in the kidneys of Akita mice. We previously showed that hydrogen peroxide is a potent stimuli for renin release from the juxtaglomerular cells, increasing plasma renin and blood pressure in mice. Thus, we hypothesized that hydrogen peroxide levels are higher in JG cells from Akita mice leading to increased renin release in this strain. Using Western Blot, we found that the NADPH oxidase isoforms NOX1 and NOX4 are expressed, but only NOX1 being upregulated in primary JG cells isolated from Akita mice, compared to JG cells from the control (C57) strain (C57=100%. Akita/NOX1= 147%±10; n=4; p<0.05). Confocal imaging showed the expression of NOX1 and NOX4 in JG cells where they both co‐localized with renin immunolabeling in renin‐containing granules. In addition, the expression of Catalase, which scavenges H202, was reduced in JG cells from diabetic Akita mice (C57=100%; Akita= 72%±7.2 of C57; n=4; p<0.05). We measured H202 levels by transducing JG cells with the fluorescent protein sensor Hyper under control of the renin1 promoter. We found that JG cells isolated from Akita mice had higher baseline levels of H202 (C57= 100, Akita=117±7%, p<0.05). Since we previously found that H202 stimulates renin release, we studied whether JG cells from Akita mice had higher total renin activity or release. For this, we measured baseline renin release to the media during 2 hours from primary JG cells cultured from Akita or control mice. JG cells were then lysed and total renin content measured. We found that in the absence of any stimuli, JG cells from Akita mice had ~2 fold higher renin release (C57= 100%, Akita=219.2±26%; p<0.04, n=6). We did not observe a significant difference in total renin content between strains. Transduction of replicate plates with adenovirus encoding Catalase (AD‐Cat) decreased baseline renin release by 35±8% (p<0.05) in JG cells from Akita mice whereas it did not affect renin release in control JG cells. We conclude that renin cells from diabetic Akita mice have higher endogenous H202 leading to increased renin release. The NADPH isoform NOX1 is enhanced in Akita mice and may be responsible for higher levels of H202 and renin release from JG cells. Our data suggest that direct stimulation of renin release by H202 could be potentially be involved in renal damage in diabetes mellitus.Support or Funding InformationNIH/NIDDK R03DK105300‐02This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Antidiabetic effects of Tetracarpidium conophorum seed on biomarkers of diabetes-induced nephropathy in rats

Objective: To investigate antidiabetic effects of Tetracarpidium conophorum seed (TECOSE) against biomarkers of diabetes-induced nephropathy in rats. Methods: Powdered seed (500 g) of TECOSE was extracted with 5 L of 100% methanol for 72 h followed by concentration of filtrate. Diabetes was induced in rats with 75 mg/kg body weight intraperitoneal streptozotocin. The rats were randomly divided into five groups (n=5 in each group) namely group A- normal control, group B- diabetic control, groups C, D and E were diabetic rats treated with 500 mg/kg body weight TECOSE orally, 7 mg/kg body weight metformin orally and subcutaneous 0.3 IU/kg body weight HumulinR, respectively. All rats were treated once daily for 2 weeks. Blood samples and urine were collected for biochemical estimations. Kidney was harvested for histomorphological studies. Results: TECOSE (500 mg/kg body weight) significantly (P<0.05) reduced blood sugar levels as effective as metformin and insulin. The plant extract also significantly (P<0.05) reduced levels of serum urea, creatinine and uric acid, proteinuria, ketonuria, hematuria and glycosuria while it significantly (P<0.05) increased glomerular filtration rate. Histomorphological study of the kidney of untreated diabetic rats showed features suggestive of glomerulosclerosis and tubular necrosis while that of treatments with TECOSE extract, metformin and insulin showed near normal histoarchitectures. Conclusions: Streptozotocin at 75 mg/kg body weight induces diabetic nephropathy in rats and TECOSE possesses potentials to prevent diabetic renal damage.

Chlorogenic acid prevents diabetic nephropathy by inhibiting oxidative stress and inflammation through modulation of the Nrf2/HO-1 and NF-ĸB pathways

Oxidative and inflammatory damage have been suggested to play important roles in the pathogenesis of diabetic nephropathy (DN). Chlorogenic acid (CGA) is one of the most abundant polyphenols and has known immunoprotective, antioxidant and anti-inflammatory properties. In the present study, animal experiments were designed to examine the protective effects of CGA in DN, and cellular experiments were designed to explore the underlying mechanisms. CGA significantly attenuated diabetic renal damage based on histological pathology and molecular biological methods. Pre-treatment with CGA increased the nuclear translocation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and the expression of heme oxygenase-1 (HO-1) and reduced the phosphorylation of IĸB and subsequent nuclear translocation of nuclear factor kappa beta (NF-ĸB). Nrf2 small interfering RNA (siRNA) and the HO-1 inhibitor zinc protoporphyrin (ZnPPIX) significantly increased the nuclear translocation of NF-ĸB and the production of pro-inflammatory cytokines in HBZY-1 cells. The NF-ĸB inhibitor pyrrolidine dithiocarbamate (PDTC) increased Nrf2 nuclear translocation and HO-1 expression and antioxidant levels. Thus, these results suggest that CGA is a potential therapeutic agent in the treatment of DN due to its antioxidant and anti-inflammatory effects which are mediated via the modulation of the Nrf2/HO-1 and NF-ĸB pathways. Moreover, CGA-induced the activation of Nrf2/HO-1,which interacts with the inhibition of NF-ĸB, as each begets and amplifies the other.

Pioglitazone ameliorates glomerular NLRP3 inflammasome activation in apolipoprotein E knockout mice with diabetes mellitus

ObjectiveThe NLRP3 inflammasome plays an important role in the pathogenesis of inflammation in diabetic nephropathy (DN). Pioglitazone (PIO) has been found to exert an anti-inflammatory effect in patients with diabetes mellitus, but it is still unclear whether PIO exhibits a similar effect in DN. We aimed to explore the effect and underlying mechanism of PIO on DN, as well as investigate if NLRP3 is a pharmacologic target of PIO.MethodsWe divided 48 apolipoprotein E (apoE) (-/-) mice into 4 groups: apoE (-/-), apoE (-/-) with PIO, diabetic apoE (-/-), and diabetic apoE (-/-) with PIO. Wild type male C57BL/6 mice were used as controls (n = 8 per group). After 8 weeks of PIO treatment, we examined the baseline characteristics and metabolic parameters of each group, and we used enzyme-linked immunosorbent assay (ELISA), western blot, and immunohistochemical staining to evaluate the expression levels of advanced glycation end products (AGEs), receptor for advanced glycation end products (RAGE), NLRP3, nuclear factor—kappa B (NF-κB), caspase-1, interleukin (IL)-18, and IL-1β in each group.ResultsCompared to the diabetic apoE (-/-) group, PIO treatment decreased blood glucose, cholesterol, serum blood urea nitrogen (BUN), and creatinine levels. It also depressed the glomerular mesangial expansion. PIO down-regulated expression of AGEs, RAGE, and NF-κB, all of which further depressed NLRP3, caspase-1, IL-18, and IL-1β levels.ConclusionPioglitazone can ameliorate diabetic renal damage, and this effect is related to the inhibition of renal AGE/RAGE axis activation and the down-regulation of NF-κB expression. These effects lead to a decline in NLRP3 levels and downstream secretion of inflammatory cytokines.

Therapeutic Potential of Chinese Prescription Hachimi-Jio-Gan and Its Crude Drug Corni Fructus against Diabetic Nephropathy

Background: Traditional plant drugs, are less toxic and free from side effects compared to general synthetic drugs. They have been used for the treatment of diabetes and associated renal damage. In this study, we evaluated effect of Hachimi-jio-gan against diabetic renal damage in a rat model of type 1 diabetic nephropathy induced by subtotal nephrectomy plus streptozotocin (STZ) injection, and in Otsuka Long-Evans Tokushima Fatty (OLETF) rats and db/db mice as a model of human type 2 diabetes, and its associated complications. To explore the active components of Hachimi-jio-gan, the antidiabetic effect of corni fructus, a consituent of Hachimi-jio-gan, and 7-O-galloyl-D-sedoheptulose, a phenolic compound isolated from corni fructus, were investigated.Methods and Results: We conducted an extensive literature search, and all required data were collected and systematically organized. The findings were reviewed and categorized based on relevance to the topic. A summary of all the therapeutic effects were reported as figures and tables.Conclusions: Hachimi-jio-gan serves as a potential therapeutic agent to against the development of type 1 and type 2 diabetic nephropathy. From the results of characterization active components of corni fructus, 7-O-galloyl-D-sedoheptulose is considered to play an important role in preventing and/or delaying the onset of diabetic renal damage. 7-O-Galloyl-D-sedoheptulose is expected to serve as a novel therapeutic agent against the development of diabetic nephropathy.

Metformin, diet tweak to treat diabetic renal damage

Metformin, diet tweak to treat diabetic renal damage

Metformin ameliorates podocyte damage by restoring renal tissue nephrin expression in type 2 diabetic rats.

Previous studies found that metformin provided some renoprotection for diabetic renal damage. In the present study, we evaluated the effects of different doses of metformin on the expression of renal tissue nephrin in type 2 diabetes mellitus (T2DM) model rats and the possible mechanism underlying its protective effect in kidney podocytes. A high-fat diet combined with a low dose of streptozotocin was used to induce T2DM model rats. Diabetic rats were treated with 150, 300, or 500 mg/kg metformin for 8 weeks. At the end of the study, urine and blood samples were collected for measurement of different indices. Light microscopy and transmission electron microscopy were used to identify morphological changes. Renal expression of nephrin protein was assayed by immunohistochemical staining, whereas real-time polymerase chain reaction was used to detect renal nephrin (Nphs1) mRNA expression. Metformin treatment of T2DM rats produced dose-dependent significant reductions in urinary albumin and nephrin concentrations, glomerular basement membrane thickness (GBMT), and the foot process fusion rate (FPFR) compared with control T2DM model rats, whereas renal expression of nephrin protein and Nphs1 mRNA was dose-dependently increased by metformin treatment. Metformin protects kidney podocytes in T2DM model rats by dose-dependently adjusting renal nephrin expression.

Corosolic acid inhibits the proliferation of glomerular mesangial cells and protects against diabetic renal damage.

Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus (DM). This study aimed to explore the effects of corosolic acid (CA) on the renal damage of DM and the mechanisms behind these effects. The renoprotective effect of CA was investigated in type 1 diabetic rats and db/db mice. The kidneys and glomerular mesangial cells (GMCs) were used to study the proliferation of GMCs by immunostaining and MTT assay. Further immunoblotting, siRNA, qPCR analysis, and detecting of NADPH oxidase activity and reactive oxygen species (ROS) generation were performed to explore relevant molecular mechanisms. In CA-treated diabetic animals, diabetes-induced albuminuria, increased serum creatinine and blood urea nitrogen were significantly attenuated, and glomerular hypertrophy, mesangial expansion and fibrosis were ameliorated. Furthermore, CA significantly inhibited proliferation of GMCs and phosphorylation of ERK1/2 and p38 MAPK in both diabetic animals and high glucose (HG)-induced GMCs. CA also normalized Δψm and inhibited HG-induced NADPH oxidase activity, ROS generation and NOX4, NOX2, p22phox and p47phox expression. More importantly, CA inhibited GMC proliferation mediated by NADPH/ERK1/2 and p38 MAPK signaling pathways. These findings suggest that CA exert the protective effect on DN by anti-proliferation resulted from inhibition of p38 MAPK- and NADPH-mediated inactivation of ERK1/2.

The correlation between urinary albumin excretion rate and the level of serum miR-130b in patients with type 2 diabetes mellitus

The aim of this study was to detect the levels of serum miR-130b expression in patients with type 2 diabetes mellitus and to analyze their correlation with diabetic renal damage.243 patients with type 2 diabetes mellitus were divided into three groups according to urinary albumin/creatinine ratio(UACR): normoalbuminuria group(UACR 300 mg/g, n=54). The levels of serum miR-130b were validated by realtime polymerase chain reaction. Serum transforming growth factor-β1(TGF-β1)and tumor necrosis factor-α(TNF-α)were determined by enzyme-linked immunosorbent assay(ELISA)in all patients and 59 healthy volunteers. Compared with control group, the level of serum miR-130b in the type 2 diabetes mellitus group were significantly decreased, gradually with the increases of UACR.The level of serum miR-130b was inversely correlated with blood urea nitrogen(r=-0.295, P<0.05), serum creatinine(r=-0.316, P<0.05), UACR(r=-0.463, P<0.05), but positively related to the estimated glomerular filtration rate(r=0.367, P<0.01). The level of serum miR-130b was also negatively correlated to homeostasis model assessment for insulin resistance, triglyceride, low density lipoprotein-cholesterol, TNF-α, and TGF-β1(r=-0.257, -0.345, -0.242, -0.562, -0.622, all P<0.01). The present study indicates that serum miR-130b might be a potential new biomarker for early diagnosis of diabetic nephropathy. Serum miR-130b might be involved in the pathogenesis of diabetic nephropathy. (Chin J Endocrinol Metab, 2016, 32: 220-223) Key words: Diabetes mellitus, type 2; Serum miR-130b; Diabetic nephropathy

Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy

The lipid lowering medication, fenofibrate (FF), is a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, possessing beneficial effects for type 2 diabetic nephropathy (DN). We investigated whether FF can prevent the development of type 1 DN, and the underlying mechanisms. Diabetes was induced by a single intraperitoneal injection of streptozotocin in C57BL/6J mice. Mice were treated with oral gavage of FF at 100mg/kg every other day for 3 and 6 months. Diabetes-induced renal oxidative stress, inflammation, apoptosis, lipid and collagen accumulation, and renal dysfunction were accompanied by significant decrease in PI3K, Akt, and GSK-3β phosphorylation as well as an increase in the nuclear accumulation of Fyn [a negative regulator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)]. All these adverse effects were significantly attenuated by FF treatment. FF also significantly increased fibroblast growth factor 21 (FGF21) expression and enhanced Nrf2 function in diabetic and non-diabetic kidneys. Moreover, FF-induced amelioration of diabetic renal damage, including the stimulation of PI3K/Akt/GSK-3β/Fyn pathway and the enhancement of Nrf2 function were abolished in FGF21-null mice, confirming the critical role of FGF21 in FF-induced renal protection. These results suggest for the first time that FF prevents the development of DN via up-regulating FGF21 and stimulating PI3K/Akt/GSK-3β/Fyn-mediated activation of the Nrf2 pathway.

Protective effect of luteolin on streptozotocin-induced diabetic renal damage in mice via the regulation of RIP140/NF-кB pathway and insulin signalling pathway

Luteolin (LUT) is one of the most common flavonoids present in various fruits and vegetables. The effects of luteolin (LUT) on streptozotocin (STZ)-induced diabetic renal damage were investigated. LUT was orally administered at 10, 20 mg/kg/day for 4 weeks to streptozotocin-induced diabetic mice. Serum levels of uric acid, creatinine, triacylglycerol, total cholesterol, low density lipoprotein and blood urea nitrogen were measured. Urinary uric acid and creatinine were assayed. Serum insulin level and oral glucose tolerance test (OGTT) were determined. Kidney pathological changes were detected. Receptor-interacting protein 140 (RIP140)/nuclear factor кB (NF-кB) pathway and insulin signalling pathway were detected. LUT restored streptozotocin-induced insulin resistance, dyslipidaemia, hyperuricemia, and renal inflammatory cell infiltration in streptozotocin-induced mice. Furthermore, LUT inhibited RIP140/NF-кB pathway and improved the insulin signalling pathway in streptozotocin-induced renal damage in mice. Thus, the beneficial effect of LUT against diabetic nephropathy (DN) is related to its regulation of RIP140/NF-кB and insulin pathway.

The renal protective effects of Anoectochilus roxburghii polysaccharose on diabetic mice induced by high-fat diet and streptozotocin

Ethnopharmacological relevanceAnoectochilus roxburghii (Wall.) Lindl. 1832 is an herbal medicine used to treat diabetes in China. Considering that Anoectochilus roxburghii polysaccharose (ARP) is the main constituent of Anoectochilus roxburghii, the present study is aimed to investigate the renal protection of ARP and its possible mechanism in diabetic mice. Materials and methodsInstitute of Cancer Research (ICR) mice were induced to diabetes with high-fat diet (HFD) and low-dose streptozotocin (STZ). ARP (100, 300mg/kg) was orally administrated to diabetic mice once a day for consecutive 15 days. The fasting glucose level, expressions of key proteins of p38 MAP kinase cascade, inflammatory factors, fibronectin (FN) and the activities of matrix metalloproteinases (MMPs) were measured. Furthermore, the histological examination of the separated kidneys was also carried out. ResultsCompared with the diabetic mice, ARP administration induced a significant decrease in blood glucose level and improved the body weight of diabetic mice. In addition, ARP inhibited the expression of renal p38 MAP kinase cascade and its downstream inflammatory factors including tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), FN as well as MMP2/9. Moreover, the histological examination showed an apparent reduction of mesangial matrix deposition and damage of microvascular structure after ARP administration. ConclusionsThe protective effects of ARP on diabetic renal damage may be attributed to the inhibition of p38 MAP kinase cascade and then attenuating the inflammatory responses and high glucose-induced renal damage.

The anti-inflammatory and antifibrotic effects of Coreopsis tinctoria Nutt on high-glucose-fat diet and streptozotocin-induced diabetic renal damage in rats.

BackgroundDiabetic nephropathy is a serious complication of diabetes whose development process is associated with inflammation, renal hypertrophy, and fibrosis. Coreopsis tinctoria Nutt, traditionally used as a healthcare tea, has anti-inflammatory, anti-hyperlipidemia, and glycemic regulation activities. The aim of our study was to investigate the renal protective effect of ethyl acetate extract of C. tinctoria Nutt (AC) on high-glucose–fat diet and streptozotocin (STZ)-induced diabetic rats.MethodsA diabetic rat model was induced by high-glucose–fat diet and intraperitoneal injection of 35 mg/kg STZ. After treatment with AC at a daily dose of 150, 300 or, 600 mg/kg for 4 weeks, metabolic and renal function parameters of serum and urine were examined. Degree of renal damage, renal proinflammatory cytokines, and fibrotic protein expression were analyzed by histopathology and immunohistochemistry. Renal AMP-activated protein kinase (AMPK) and transforming growth factor (TGF)-β1/Smad signaling pathway were determined by western blotting.ResultsDiabetic rats showed obvious renal dysfunction, inflammation and fibrosis. However, AC significantly reduced levels of blood glucose, total cholesterol, triglyceride, blood urea nitrogen, serum creatinine and urinary albumin, as well as expression of kidney proinflammatory cytokines of monocyte chemoattractant protein-1 and intercellular adhesion molecule-1. AC also ameliorated renal hypertrophy and fibrosis by reducing fibronectin and collagen IV and suppressing the TGF-β1/Smad signaling pathway. Meanwhile, AMPKα as a protective cytokine was markedly stimulated by AC.ConclusionIn summary, AC controls blood glucose, inhibits inflammatory and fibrotic processes, suppresses the TGF-β1/Smad signaling pathway, and activates phosphorylation of AMPKα in the kidneys, which confirms the protective effects of AC in the early stage of diabetic kidney disease.

Amelioration of experimentally induced diabetic nephropathy and renal damage by nilotinib.

Diabetes mellitus is an ever growing world-wide health problem. The patient has to stick to a firm life-long therapeutic regimen, otherwise diabetic complications will develop. Diabetic nephropathy (DN) is one of the most common diabetic complications and it requires careful medical attendance. Nilotinib hydrochloride is a protein tyrosine kinase inhibitor reported to have numerous therapeutic efficacies besides being an anticancer. In the current study, single I.P. streptozotocin (50 mg/kg) injection was used to induce type I diabetes mellitus in male Sprague-Dawley rats. After 8 weeks, significant deterioration of renal function with urinary excretion of nephrin, podocalyxin, and albumin was observed. Daily oral administration of nilotinib (20 mg/kg) for 8 weeks significantly improved signs of DN on all investigated scales. On a biochemical scale, kidney functions, albuminuria, urinary nephrin, podocalyxin excretion, and host oxidant/antioxidant balance significantly improved. Kidney content of nitric oxide, expression of toll-like receptors 4 and NF-κB/p65 activity significantly declined as well. On a histopathological scale, α-smooth muscle actin and nestin expression significantly declined. Meanwhile, area of fibrosis significantly declined as seen with significant reduction in accumulation of extracellular matrix components and kidney content of collagen. Ultimately, such improvements were accompanied by significant restoration of normal kidney physiology and function. In conclusion, nilotinib can hinder progression of DN through various mechanisms. Reduction of oxidative stress, enhancement of host antioxidant defense system, reduction of inflammation, angiogenesis, tissue hypoxia, and pro-fibrogenic biomarker expression can be implicated in the beneficial therapeutic outcome observed with nilotinib therapy.

Hydrogen Sulfide Inhibits Ca2+‐induced M itochondrial Permeability Transition Pore Opening in Type‐1 Diabetes

Hydrogen sulfide (H2S) attenuates N‐Methyl‐D‐Aspartate receptor (NMDA‐R) and mitigates diabetic renal damage but the molecular mechanism is not known. While NMDA‐R facilitates Ca2+ permeability, H2S is known to inhibit L‐type Ca2+ channel. High Ca2+ activates cyclophilin D (CyPD), a gatekeeper protein of mitochondrial permeability transition pore (mPTP), thus facilitating molecular exchange between matrix and cytoplasm causing oxidative outburst and cell death. We tested the hypothesis that NMDA‐R mediates Ca2+ influx causing CyPD activation and mPTP opening leading to oxidative stress and diabetic renal injury. H2S treatment blocks Ca2+ channel and thus inhibits CyPD and mPTP opening and reduces renal damage. C57BL/6J and Akita (C57BL/6J‐Ins2Akita) mice were treated without or with H2S donor (GYY4137, 0.25mg/Kg/day) intra‐peritoneally for 4 weeks. In vitro studies were performed using mouse glomerular endothelial cells. Low levels of H2S and increased expression of NMDA‐R1 in diabetes induced Ca2+ permeability, which was ameliorated by H2S treatment. We observed cytosolic Ca2+ influx in hyperglycemia along with mt‐CyPD activation, increased mPTP opening and oxidative outburst which were reversed after H2S treatment. Renal injury biomarker, KIM‐1 was up regulated in diabetes and decreased after H2S treatment. Inhibition of NMDA‐R by pharmacological blocker, MK‐801 revealed similar results. We conclude that NMDA‐R1 mediated Ca2+ influx in diabetes induces mPTP opening via CyPD activation leading to increased oxidative stress and renal injury. We provide further evidence that H2S protects diabetic kidney by blocking mitochondrial Ca2+ permeability through NMDA‐R1 pathway.

Diabetic nephropathy: current diagnostics and treatment

Diabetic kidney disease is a leading cause of renal failure in Germany. Albuminuria is an early diagnostic indicator of renal damage in diabetes and, aside from renal failure, a major risk factor of cardiovascular disease. An early diagnosis of diabetic kidney disease is of great importance to reduce associated cardiovascular mortality; glycemic control should aim for HbA1c levels of < 7 %. Guidelines on blood pressure differ, but it should generally be reduced to < 140/90mmHg; stricter limits should be applied if albuminuria is present. ACE inhibitors (ACE-I) or angiotensin receptor blockers (ARB) should be preferred for blood pressure control. A combination of ACE-Is and ARBs or a renin-inhibitor therapy does not improve cardiovascular outcome, instead it increases the rate of adverse events, e.g., hyperkalemia or renal failure. Lipid control, usually with statins, should be started at an early phase of renal failure. VitaminD receptor activation and uric acid reduction might play a future role in the treatment of diabetic kidney disease. Pharmacological modification of inflammatory signaling appears to be promising but is not yet of clinical relevance.

Polysaccharides from Liriopes Radix ameliorate streptozotocin-induced type I diabetic nephropathy via regulating NF-κB and p38 MAPK signaling pathways.

BackgroundThe polysaccharides from Liriopes Radix (PSLR) has been indicated to ameliorate insulin signaling transduction and glucose metabolism. We aimed to investigate whether PSLR exerts an ameliorative effect on renal damage in diabetes induced by streptozotocin.MethodsDiabetes was induced with STZ (60 mg/kg) by intraperitoneal injection in rats. Two weeks after STZ injection, rats in the treatment group were orally dosed with PSLR (200 and 300 mg/kg/day for 8 weeks. The normal rats were chosen as nondiabetic control group. Changes in renal function-related parameters in plasma and urine were analyzed at the end of the study. Kidneys were isolated for pathology histology, immunohistochemistry, and Western blot analyses.ResultsDiabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, blood urea nitrogen and proteinuria, along with marked elevation in the ratio of kidney weight to body weight. All of these abnormalities were significantly reversed by PSLR. The histological examinations revealed amelioration of diabetes-induced glomerular pathological changes following treatment with PSLR. The less protein expressions of renal nephrin and podocin in diabetic rats were increased following treatment with PSLR. PSLR reduced the accumulation of ED-1-expressing macrophages in renal tissue of diabetic rats. PSLR almost completely abolished T cells infiltration and attenuated the expression of proinflammatory cytokines. PSLR treatments not only reduced the degradation of inhibitory kappa B kinase, but also downregulated the protein expression of nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) in diabetic kidney.ConclusionsThe results suggest that the renal protective effects of PSLR occur through improved glycemic control and renal structural changes, which are involved in the inhibition of NF-κB and p-38 MAPK mediated inflammation.

Daily exercise training protects against albuminuria and angiotensin converting enzyme 2 shedding in db/db diabetic mice.

Angiotensin II (Ang II) is involved in induction and progression of renal damage in diabetes. Angiotensin converting enzyme 2 (ACE2) is highly expressed in the kidney and has been shown to be renoprotective by degrading Ang II to Ang-(1-7). A disintegrin and metalloproteinase 17 (ADAM17)-mediated shedding of renal ACE2 contribute to diabetic nephropathy pathogenesis. Lifestyle modification and metformin are recommended as initial therapies for most patients with type 2 diabetes. The aim of this study was to investigate whether exercise training and/or metformin improve glucose homeostasis and albuminuria and downregulate renal ADAM17 and ACE2 shedding in db/db mice. Seven-week-old normal and db/db mice were subjected either to a sedentary existence or exercise training with and without metformin (150 mg/kg per day) for 10 weeks. Exercise training significantly lowered blood glucose, urinary albumin and ACE2 excretion in db/db mice. ADAM17 and ACE2 proteins were co-localized in cortical tubules of the kidney, indicating a possible interaction. Metformin treatment was effective in lowering hyperglycemia only during the first 2 weeks of treatment. Increased renal ADAM17 in 17-week-old db/db mice was corrected by physical exercise but not metformin. In addition, exercise training reduced plasma triglycerides and enhanced insulin levels of db/db mice. In conclusion, exercise training alone and in combination with metformin prevented shedding of renal ACE2 by decreasing ADAM17 protein. Urinary ACE2 could serve as a prognostic tool for the progression of kidney damage and its attenuation by exercise may partially contribute to its renal protection.

Protective Effect of Esculin on Streptozotocin-Induced Diabetic Renal Damage in Mice

The present study investigated the presence and mechanism of esculin-mediated renoprotection to assess its therapeutic potential. Esculin was orally administered at 20 mg/kg/day for 2 weeks to streptozotocin-induced diabetic mice, and its effects were compared with those of the vehicle in normal and diabetic mice. After oral administration of esculin to mice, the concentrations of esculin and esculetin in blood were 159.5 ± 29.8 and 9.7 ± 4.9 ng/mL at 30 min, respectively. Food and water intake were significantly increased in the diabetic mice compared to normal mice but attenuated in mice receiving esculin. The elevated blood glucose level and hepatic glucose-6-phosphatase expression were significantly reduced in esculin-treated diabetic mice, supporting the antidiabetic effect of esculin. Esculin also increased the uptake of glucose and induced the insulin-evoked phosphorylation of insulin receptor, Akt, and glycogen synthase kinase 3β in C2C12 myotubes, indicating a potential for improvement of insulin sensitivity. In addition, esculin lessened the elevated blood creatinine levels in diabetic mice and ameliorated diabetes-induced renal dysfunction by reducing caspase-3 activation in the kidney. Data support the beneficial effect of esculin against diabetes and oxidative stress-related inflammatory processes in the kidney.

Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes

Sirtuin 1 (Sirt1), a NAD(+)-regulated deacetylase with numerous known positive effects on cellular and whole-body metabolism, is expressed in the renal cortex and medulla. It is known to have protective effects against age-related disease, including diabetes. Here we investigated the protective role of Sirt1 in diabetic renal damage. We found that Sirt1 in proximal tubules (PTs) was downregulated before albuminuria occurred in streptozotocin-induced or obese (db/db) diabetic mice. PT-specific SIRT1 transgenic and Sirt1 knockout mice showed prevention and aggravation of the glomerular changes that occur in diabetes, respectively, and nondiabetic knockout mice exhibited albuminuria, suggesting that Sirt1 in PTs affects glomerular function. Downregulation of Sirt1 and upregulation of the tight junction protein Claudin-1 by SIRT1-mediated epigenetic regulation in podocytes contributed to albuminuria. We did not observe these phenomena in 5/6 nephrectomized mice. We also demonstrated retrograde interplay from PTs to glomeruli using nicotinamide mononucleotide (NMN) from conditioned medium, measurement of the autofluorescence of photoactivatable NMN and injection of fluorescence-labeled NMN. In human subjects with diabetes, the levels of SIRT1 and Claudin-1 were correlated with proteinuria levels. These results suggest that Sirt1 in PTs protects against albuminuria in diabetes by maintaining NMN concentrations around glomeruli, thus influencing podocyte function.