STZ-induced Diabetic Nephropathy Research Articles

A Therapeutic Approach of Chitosan-loaded p-Coumaric Acid Nanoparticles to Alleviate Diabetic Nephropathy in Wister Rats.

This study evaluated the renoprotective effects of p-Coumaric acid nanoparticles (PCNPs) in nephropathic rats. Six groups of male Albino Wistar rats were randomly assigned. Group 1 was the control, while Group 2 received 45 mg/kg of streptozotocin (STZ) to induce diabetic nephropathy. Groups 3, 4, and 5 received STZ (45 mg/kg) along with PCNPs at doses of 20, 40, and 80 mg/kg, respectively. Group 6 received 80 mg/kg of PCNPs without STZ. Body weight, blood glucose, insulin, hemoglobin (Hb), and glycosylated hemoglobin (HbA1c) levels were measured. Blood urea, serum creatinine, kidney antioxidant enzymes, and lipid peroxidation levels were also analyzed. Histological and immunohistochemical studies of kidney tissues were performed. PCNPs (80 mg/kg) significantly reduced serum glucose, creatinine, and urea levels while increasing insulin levels and antioxidant activity in the kidneys. Histological analysis revealed that nephropathic rats exhibited cellular damage, including shrinkage of Bowman's capsule and lesions in the kidneys, along with degeneration in the Islets of Langerhans in the pancreas. PCNPs treatment restored these morphological alterations in the pancreas, liver, and kidneys to near-normal. Furthermore, nephropathic rats had elevated IL-6 and TNF-α expression in the renal tubules and glomeruli, which was reduced following PCNPs treatment. The findings suggest that PCNPs exhibit antihyperglycemic, antioxidant, antiglycation, and renoprotective effects in STZ-induced diabetic nephropathy.

Isoferulic acid regulates CXCL12/CXCR4-mediated apoptosis and autophagy in podocyte and mice with STZ-induced diabetic nephropathy

Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus and a major cause of end-stage renal disease. Isoferulic acid (IFA) is a phenolic compound that has strong antioxidant, anti-inflammatory, and hypoglycemic effects. Researches and our previous study showed the potential anti-diabetic capacity and anti- oxidative stress damage targeting podocytes of IFA. The purpose of this study was to investigate whether IFA protects MPC5 podocytes from high glucose damage and alleviates DN symptoms in STZ-induced mice, as well as to explore the mechanism. The findings revealed that IFA (10, 25, 50μM) significantly reduced high glucose-mediated toxicity, abnormal motility and morphology, ROS release, Ca2+ elevation with MPTP opening, apoptotic alterations with Caspase-3/7 activity increase and CXCL12 chemotaxis and interaction with CXCR4 in MPC5 podocytes. Furthermore, IFA increased Podocalyxin and LC3 II/I ratio. Meanwhile, IFA suppressed p53, mTOR, CASK, and p62. Furthermore, IFA has the ability to directly influence downstream mTOR, p53, and CASK apoptotic and podocyte motility regulatory targets when inhibiting the CXCL12/CXCR4 signaling pathway. In the sequent in vivo experiment, the results showed STZ-induced DN mice had higher kidney index, urination, UACR, lipid metabolism abnormalities and renal dysfunction, raised blood glucose, and podocyte damage than normal C57BL/6 mice. However, IFA treatment (50mg/kg, 25mg/kg, and 12.5mg/kg) for 10weeks restored the DN symptoms in the mice. IFA treatment elevated LC3B and LC3 II/I ratios and decreased p62 via suppressing chemokine axis CXCL12/CXCR4 with PI3K/Akt/mTOR, MMP9, and NF-κB p65 and activating podocyte markers WT1, nephrin, and Podocalyxin, thereby inducing autophagy and mitigating apoptosis in the DN mice kidneys. These findings suggest that IFA protective mechanism on kidney and podocytes simulating DN symptoms is primarily mediated by the CXCL12/CXCR4 pathways with the inactivation of apoptotic pathways and activation of autophagy.

Alogliptin attenuates STZ-induced diabetic nephropathy in rats through the modulation of autophagy, apoptosis, and inflammation pathways: Targeting NF-κB and AMPK/mTOR pathway.

Diabetic nephropathy (DN) is a type of microvascular complication that arises from diabetes mellitus and leads to further health issues. Most importantly, the prevalence of DN is steadily rising in developed countries. This research explored the therapeutic benefits of alogliptin, a dipeptidyl peptidase IV (DPP-4) inhibitor, on streptozotocin (STZ)-induced DN and its underlying mechanisms in rats. Ten rats were allocated to group 1, served as the normal group; and received saline. To develop diabetes, thirty rats were administered a single intraperitoneal dose of STZ (45mg/kg). STZ-induced diabetic rats were randomly assigned to three groups: group 2 diabetic control; was given saline, groups 3 and 4 received alogliptin (10mg/kg) and (20mg/kg), respectively. The treatment began 8weeks after diabetes onset and continued for four weeks. Histopathological alterations in the kidney were detected. Serum was collected to measure blood glucose levels (BGL), renal function, and lactate dehydrogenase (LDH). Tissue samples were collected to detect changes in oxidative stress (OS), inflammation, 5' adenosine monophosphate-activated protein kinase (AMPK), and the mammalian target of Rapamycin (mTOR) signaling pathways in addition to apoptotic and autophagy changes. Alogliptin reduced STZ-induced histological changes in the kidney as well as OS, and inflammation. Alogliptin also ameliorated the AMPK/mTOR signaling pathways, enhanced autophagy, and reduced apoptosis. These results demonstrate that alogliptin ameliorates inflammation and OS and consequently modulates the AMPK/mTOR axis along with targeting autophagy and apoptosis, leading to the alleviation of DN.

Potent anti-inflammatory and anti-apoptotic activities of electrostatically complexed C-peptide nanospheres ameliorate diabetic nephropathy

In the present era of "Diabetic Pandemic", peptide-based therapies have generated immense interest however, are facing odds due to inevitable limitations like stability, delivery complications and off-target effects. One such promising molecule is C-peptide (CPep, 31 amino acid polypeptide with t1/2 30min); it is a cleaved subunit of pro-insulin, well known to suppress microvascular complications in kidney but has not been able to undergo translation to the clinic till date. Herein, a polymeric CPep nano-complexes (NPX) was prepared by leveraging electrostatic interaction between in-house synthesized cationic, polyethylene carbonate (PEC) based copolymer (Mol. wt. 44,767Da) and negatively charged CPep (Mol. wt. 3299Da) at pH7.4 and further evaluated in vitro and in vivo. NPX exhibited a spherical morphology with a particle size of 167nm and zeta potential equivalent to +10.3, with 85.70% of CPep complexation efficiency. The cellular uptake of FITC-tagged CPep NPX was 95.61% in normal rat kidney cells, NRK-52E. Additionally, the hemocompatible NPX showed prominent cell-proliferative, anti-oxidative (1.8 folds increased GSH; 2.8 folds reduced nitrite concentration) and anti-inflammatory activity in metabolic stress induced NRK-52E cells as well. The observation was further confirmed by upregulation of anti-apoptotic protein BCl2 by 3.5 folds, and proliferative markers (β1-integrin and EGFR) by 3.5 and 2.3 folds, respectively, compared to the high glucose treated control group. Pharmacokinetic study of NPX in Wistar rats revealed a 6.34 folds greater half-life than free CPep. In in-vivo efficacy study in STZ-induced diabetic nephropathy animal model, NPX reduced blood glucose levels and IL-6 levels significantly by 1.3 and 2.5 folds, respectively, as compared to the disease control group. The above findings suggested that NPX has tremendous potential to impart sustained release of CPep, resulting in enhanced efficacy to treat diabetes-induced nephropathy and significantly improved renal pathology.

Harmine alleviated STZ-induced rat diabetic nephropathy: A potential role via regulating AMPK/Nrf2 pathway and deactivating ataxia-telangiectasia mutated (ATM) signaling

Diabetic nephropathy (DN) is a serious kidney disorder driven by diabetes and affects people all over the world. One of the mechanisms promoting NF-κB-induced renal inflammation and injury has been theorized to be ATM signaling. On the other hand, AMPK, which can be activated by the naturally occurring alkaloid harmine (HAR), has been proposed to stop that action. As a result, the goal of this study was to evaluate the therapeutic effectiveness of HAR against streptozotocin (STZ)-induced DN in rats through AMPK-mediated inactivation of ATM pathways. Twenty male Wistar rats were grouped into 4 groups, as follow: CONT, DN, HAR (10mg/kg), DN+HAR, where HAR was daily administered I.P. once for 2weeks. The renal AMPK and PGC-1α expressions, as well as Sirt1 levels, were assessed. To ascertain the oxidative reactions, renal Nrf2 expression, HO-1, MDA, and TAC concentrations were measured. As parts of ATM pathways, ATM and p53 expressions, in addition to GSK-3β levels were determined. Renal expression of NEMO, TNF-α, and IL-6 levels were also estimated. Moreover, histopathological and immunohistochemical detection of Bcl-2, Bax, and caspase 3 were reported. Results indicated that HAR intake notably alleviated STZ-induced kidney damage by triggering AMPK and Sirt1, which in turn boosted PGC-1α, improved NRf2/HO-1 axis, and lowered ROS production. As a consequence, HAR blocked the ATM-triggered renal inflammation and minimized caspase-3 expression by repressing the Bax/Bcl2 ratio. Because of its ability to activate AMPK/Nrf2 axis, HAR may represent an emerging avenue for future DN therapy by blocking ATM pathways.

Partridge tea polyphenols alleviated STZ-induced diabetic nephropathy by regulating Keap1/Nrf2/ARE signaling pathway in C57BL/6 mice

Partridge tea polyphenols alleviated STZ-induced diabetic nephropathy by regulating Keap1/Nrf2/ARE signaling pathway in C57BL/6 mice

Eco-friendly Nanoparticles Synthesized from Salvia sclarea Ethanol Extract Protect against STZ-induced Diabetic Nephropathy in Rats via Antioxidant, Anti-inflammatory, and Apoptosis Mechanisms

Recent global scientific attention has been directed towards eco-friendly synthesis and versatile applications of silver nanoparticles (AgNPs) due to their effectiveness against specific cells and tissues. This study aimed to develop a green synthesis method for AgNPs using ethanolic extract from Salvia sclarea aerial parts, and to assess their protective efficacy against streptozotocin (STZ)-induced diabetic nephropathy in rats. Additionally, antioxidant, anti-inflammatory, and apoptosis studies were conducted to understand their mode of action. Characterization via ultraviolet-visible (UV-Vis) spectroscopy, infrared (IR) spectroscopy, and X-ray diffraction (XRD) confirmed the formation of ethanol extract of Salvia sclarea silver nanoparticles (EESS AgNPs), with a distinctive absorption peak at 400 nm. Scanning electron microscopy (SEM) analysis revealed predominantly spherical and quasi-spherical shapes of the synthesized nanoparticles. The treatment procedure spanned for a period of 12 weeks in diabetic rats and were evaluated for inflammatory markers (tumor necrosis factor-α, antioxidant markers (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH) and apoptosis markers (Bcl-2, Bax, cleaved-caspase-3). Results demonstrated that treatment with EESS AgNPs significantly reduced blood glucose levels compared to the diabetic group. Additionally, EESS AgNPs treatment led to a significant decrease in levels of pro-inflammatory cytokines TNF-α, IL-1β, and PKC-ꞵ in renal cells. Furthermore, EESS AgNPs effectively modulated antioxidant enzyme concentrations, including GSH, SOD, GPx, and CAT, bringing them to acceptable levels. Administration of EESS AgNPs also resulted in a significant decrease in protein levels of Bax and activated caspase-3, while increasing expression of the anti-apoptotic protein Bcl-2 in renal cells of STZ-induced diabetic rats. In conclusion, EESS AgNPs demonstrate potent anti-hyperglycemic effects, potentially mitigating diabetic nephropathy by suppressing hyperglycemiainduced oxidative stress, apoptosis, and inflammation in renal cells of diabetic rats.

Renoprotective Effect of Thymoquinone against Streptozotocin-Induced Diabetic Nephropathy: Role of NOX2 and Nrf2 Signals.

Diabetic nephropathy is an unavoidable complication of chronic uncontrolled diabetes mellitus. The pathogenesis of diabetic nephropathy is multifactorial, and the development of an effective therapy remains to be elucidated. The aim of the present study was to assess the role of NOX2 and Nrf2 in the protective mechanism of thymoquinone (THQ) against streptozotocin (STZ)-induced diabetic nephropathy. Rats were injected with STZ (55 mg/kg) to induce diabetes. The diabetic rats were orally treated with THQ (10 mg/kg/day) for eight weeks. STZ-treated rats exhibit an elevation of serum creatinine, serum urea, and creatinine clearance. The renal abnormalities were associated with increased NADPH oxidase isoform, NOX2 protein expression, and activity, along with elevated malondialdehyde (MDA). In addition, the tumor necrotic factor-alpha (TNF-α) level and nitric oxide (NO) bioavailability, as well as the transforming growth factor-beta (TGF)-β, were markedly increased. On the other hand, the nuclear factor-E2-related factor (Nrf2) protein expression was significantly reduced in diabetic rats compared to the control. However, treatment with THQ significantly reversed these alterations with subsequent ameliorating renal dysfunction and pathological abnormalities. The present study demonstrates that THQ could protect against STZ-induced diabetic nephropathy by modulating the Nrf2/NOX2 signaling pathway.

Regulation of PKC/TLR-4/NF-kB signaling by sulbutiamine improves diabetic nephropathy in rats

One of the serious complications of diabetes mellitus is diabetic nephropathy (DN) which may finally lead to renal failure. The current study aimed to explore the effect of sulbutiamine, a synthetic derivative of vitamin B1, in streptozotocin (STZ)-induced DN and related pathways. Experimental DN was successfully induced 8 weeks after a single low dose of STZ (45mg/kg, I.P.). Four groups of rats were used in this study and divided randomly into: control group, diabetic group, sulbutiamine control (control+sulbutiamine) group, and sulbutiamine-treated (60mg/kg) (diabetic+sulbutiamine) group. The fasting blood glucose level (BGL), the levels of kidney injury molecule-1 (Kim-1), urea and creatinine in serum, as well as the renal content of malondialdehyde (MDA), protein kinase C (PKC), toll-like receptor-4 (TLR-4) and nuclear factor kappa B (NF-κB) were determined. Additionally, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and transforming growth factor-β1 (TGF-β1) contents were evaluated immunohistochemically. Sulbutiamine treatment decreased fasting BGL and improved the kidney function tests compared to diabetic rats. Moreover, TLR-4, NF-κB, MDA and PKC contents were substantially reduced following sulbutiamine treatment compared to the diabetic group. Sulbutiamine managed to obstruct the production of the pro-inflammatory TNF-α and IL-1β and suppressed TGF-β1 level, in addition to attenuating the histopathological changes associated with DN. This study revealed, for the first time, the ability of sulbutiamine to ameliorate STZ-induced diabetic nephropathy in rats. This nephroprotective outcome of sulbutiamine against DN may be attributed to glycemic control in addition to its anti-oxidative, anti-inflammatory and anti-fibrotic effects.

Effect of Selenium Nanoparticles and/or Bee Venom against STZ-Induced Diabetic Cardiomyopathy and Nephropathy.

The main purpose of our study was to examine the role of selenium nanoparticles (SeNPs) and/or bee venom (BV) in ameliorating diabetic cardiomyopathy (DCM) and nephropathy (DN) at the biochemical, histopathological and molecular levels. Fifty male albino rats were used in this experiment, divided into five groups: control, Streptozocin (STZ) diabetic, STZ-diabetic treated with SeNPs, STZ-diabetic treated with BV, and STZ-diabetic treated with SeNPs and BV. Biochemically, STZ injection resulted in a significant increase in serum glucose, BUN, creatinine, CRP, CK-MB, AST, LDH and cardiac troponins with a significant decrease in the serum insulin and albumin concentrations. Histopathologically, STZ injection resulted in diabetes, as revealed by glomerulonephritis, perivascular hemorrhage, inflammatory cell infiltrations and fibrosis, with widening of interstitial spaces of cardiomyocytes, loss of muscle cells continuity and some hyaline degeneration. At the molecular levels, the expression levels of miRNA 328, miRNA-21, TGFβ1, TGFβ1R, JAK1, STST-3, SMAD-1 and NFκβ genes were significantly up-regulated, whereas the expression levels of SMAD-7 were significantly down-regulated. It is concluded that SeNPs and/or BV administration ameliorates the deleterious effects resulting from STZ administration through improving the biochemical, histopathological and molecular effects, suggesting their protective role against the long-term diabetic complications of DCM and DN.

Rutin and selenium nanoparticles protected against STZ-induced diabetic nephropathy in rats through downregulating Jak-2/Stat3 pathway and upregulating Nrf-2/HO-1 pathway

Diabetic nephropathy (DN) is a renal complication of diabetic hyperglycemia. The Signal transducer and activator of transcription 3 (Stat3) is a center molecule of the chronic inflammation causing DN progression. Therefore, the study investigated the possible inhibitory effects of Rutin (Ru) and Selenium (Se), formulated as nanoparticles (SeNPs), on Stat3 pathway in streptozotocin (STZ)-induced DN in Sprague-Dawley rats. Ru (100mg/kg/orally) and SeNPs (equivalent to 5mg of Se/kg/orally) were given as treatment for eight weeks. An assessment of fasting blood glucose, renal function biomarkers, GSH, and MDA was carried out spectrophotometrically. ELISA assessment of renal IL-6, NF-κB, TNF-α, Jak-2, and p-Stat3 was performed. Sirt-1, Nrf-2, and HO-1 were assessed immunohistochemically. DN group receiving Ru+SeNPs showed a decrease in fasting blood glucose, serum creatinine, and urea (163.8±22.8, 0.54±0.1, and 53.6±25.7mg/dl, respectively), compared to the DN group (443.8±42.72, 1.58±0.4, and 281.8±47.35mg/dl, respectively). In addition, it exhibited elevation in the levels of Sirt-1, Nrf-2 and HO-1 compared to the DN group. Finally, Ru+SeNPs exhibited a significant reduction in IL-6, NF-κB, TNF-α, Jak-2, and p-Stat3 (42.8±10.3, 1.2±0.1, 53.4±3.87, 0.8±0.06 and 1.1±0.2 U/g tissue, respectively) when compared to the DN group (155.3±13.97, 2.8±0.3, 105.5±32.84, 2.03±0.2 and 2.56±0.15 U/g tissue, respectively). Therefore, combining Ru with SeNPs has a potential renoprotective effect against DN by upregulating Nrf-2/HO-1 and downregulating Jak-2/Stat3 Pathways.

Rosuvastatin Induces Renal HO-1 Activity and Expression Levels as a Main Protective Mechanism against STZ-Induced Diabetic Nephropathy.

Background and Objectives: Nephroprotective effect of statins is still controversial. The aim of this study was to investigate the possible hemin-like nephroprotective effect of rosuvastatin (RSV) in streptozotocin (STZ)-induced diabetic rats. Materials and Methods: DN was induced in rats via a single dose of 50 mg/kg STZ i.p., with or without RSV (10 mg/kg orally) for 30 days. To investigate hemin-like effect of RSV on renal heme oxygenase-1 (HO-1), RSV was administered in the presence or absence of an inhibitor of HO-1; zinc protoporphyrin-XI (ZnPP), in a dose of 50 µmol/kg i.p. Results: Induction of diabetes with STZ caused, as expected, significant hyperglycemia, as well as deteriorated kidney function, lipid profile and histopathological architecture. The DN group also showed renal oxidative stress, indicated by decreased superoxide dismutase, catalase, and reduced glutathione, with increased malondialdehyde, myeloperoxidase and nitric oxide. Renal expression of inflammatory marker TNF-α, and pro-apoptotic marker caspase 3, were also increased in the DN group. Administration of RSV in DN rats did not improve glucose level but succeeded in recovering kidney function and normal structure as well as improving the lipid profile. RSV also improved renal oxidative, inflammatory, and apoptotic statuses. Interestingly, the administration of RSV increased renal expression and activity of HO-1 compared to the untreated DN group. Co-administration of ZnPP blocked the effect of RSV on HO-1 and deteriorated all RSV favorable effects. Conclusions: RSV can protect against DN, at least in part, via increasing renal HO-1 expression and/or activity, which seems to be upstream to RSV antioxidant, anti-inflammatory, and anti-apoptotic effects.

Anti-Hyperglycemic Effects of Refined Fractions from Cyclocarya paliurus Leaves on Streptozotocin-Induced Diabetic Mice.

To identify the chemical components responsible for the anti-hyperglycemic effect of Cyclocarya paliurus (Batal.) Iljinsk (Juglandaceae) leaves, an ethanol extract (CPE) and a water extract (CPW) of C. paliurus leaves, as well as their total flavonoids (CPF), triterpenoids (CPT) and crude polysaccharides (CPP), were prepared and assessed on streptozotocin (STZ)-induced diabetic mice. After being orally administrated once a day for 24 days, CPF (300 mg/kg), CPP (180 mg/kg), or CPF+CPP (300 mg/kg CPF + 180 mg/kg CPP) treatment reversed STZ-induced body weight and muscle mass losses. The glucose tolerance tests and insulin tolerance tests suggested that CPF, CPP, and CPF+CPP showed anti-hyperglycemic effect in STZ-induced diabetic mice. Furthermore, CPF enhances glucose-stimulated insulin secretion in MIN6 cells and insulin-stimulated glucose uptake in C2C12 myotubes. CPF and CPP suppressed inflammatory cytokine levels in STZ-induced diabetic mice. Additionally, CPF and CPP improved STZ-induced diabetic nephropathy assessed by H&E staining, blood urea nitrogen content, and urine creatinine level. The molecular networking and Emperor analysis results indicated that CPF showed potential anti-hyperglycemic effects, and HPLC–MS/MS analysis indicated that CPF contains 3 phenolic acids and 9 flavonoids. In contrast, CPT (650 mg/kg) and CPC (300 mg/kg CPF + 180 mg/kg CPP + 650 mg/kg CPT) did not show anti-hyperglycemic effect. Taken together, polysaccharides and flavonoids are responsible for the anti-hyperglycemic effect of C. paliurus leaves, and the clinical application of C. paliurus need to be refined.

Buyang Huanwu Decoction protects against STZ-induced diabetic nephropathy by inhibiting TGF-\u03b2/Smad3 signaling-mediated renal fibrosis and inflammation

BackgroundBuyang Huanwu Decoction (BHD) is a classical Chinese Medicine formula empirically used for diabetic nephropathy (DN). However, its therapeutic efficacies and the underlying mechanisms remain obscure. In our study, we aim to evaluate the renoprotective effect of BHD on a streptozotocin (STZ)-induced diabetic nephropathy mouse model and explore the potential underlying mechanism in mouse mesangial cells (MCs) treated with high glucose in vitro, followed by screening the active compounds in BHD.MethodsMice were received 50 mg/kg streptozotocin (STZ) or citrate buffer intraperitoneally for 5 consecutive days. BHD was intragastrically administrated for 12 weeks starting from week 4 after the diabetes induction. The quality control and quantitative analysis of BHD were studied by high-performance liquid chromatography (HPLC). Renal function was evaluated by urinary albumin excretion (UAE) using ELISA. The mesangial matrix expansion and renal fibrosis were measured using periodic acid-schiff (PAS) staining and Masson Trichrome staining. Mouse mesangial cells (MCs) were employed to study molecular mechanisms.ResultsWe found that the impaired renal function in diabetic nephropathy was significantly restored by BHD, as indicated by the decreased UAE without affecting the blood glucose level. Consistently, BHD markedly alleviated STZ-induced diabetic glomerulosclerosis and tubulointerstitial injury as shown by PAS staining, accompanied by a reduction of renal inflammation and fibrosis. Mechanistically, BHD inhibited the activation of TGF-β1/Smad3 and NF-κB signaling in diabetic nephropathy while suppressing Arkadia expression and restoring renal Smad7. We further found that calycosin-7-glucoside (CG) was one of the active compounds from BHD, which significantly suppressed high glucose-induced inflammation and fibrosis by inhibiting TGF-β1/Smad3 and NF-κB signaling pathways in mesangial cells.ConclusionBHD could attenuate renal fibrosis and inflammation in STZ-induced diabetic kidneys via inhibiting TGF-β1/Smad3 and NF-κB signaling while suppressing the Arkadia and restoring renal Smad7. CG could be one of the active compounds in BHD to suppress renal inflammation and fibrosis in diabetic nephropathy.

The Prospective Ameliorative Role of Zinc Oxide Nanoparticles in STZ-Induced Diabetic Nephropathy in Rats: Mechanistic Targeting of Autophagy and Regulating Nrf2/TXNIP/NLRP3 Inflammasome Signaling.

Diabetic nephropathy (DN) as one of the common microvascular complications of diabetes mellitus, is the main cause of end-stage renal disease. Zinc oxide nanoparticles (ZnO NPs) have been employed in several biomedical aspects. This study purposed to explore the mechanistic renoprotective effects of ZnO NPs in STZ-induced DN. Sixty male Wistar rats were allocated into four equal groups: control, ZnO NPs control, STZ, and STZ + ZnO NPs groups. At the end of the experiment, blood and urine biochemical parameters were assayed. Renal tissue level of advanced glycation end products (AGEs) was assayed spectrofluorometrically, moreover, nuclear factor erythroid 2-related factor 2 (Nrf2) DNA-binding activity and IL-1β levels were detected by ELISA. The gene expression levels of thioredoxin-interacting protein (TXNIP) and NOD-like receptor family pyrin domain containing 3 (NLRP3) were detected by quantitative real-time PCR. Oxidative stress markers were determined spectrophotometrically. Also, renal tissue histopathological and immunohistochemical analyses were determined. After 6weeks of treatment, ZnO NPs markedly improved the biochemical, renal functions, and histopathological findings. Furthermore, ZnO NPs significantly increased Nrf2-DNA-binding activity and downregulated TXNIP gene expression leading to restoration of the redox status. Additionally, ZnO NPs ameliorated AGEs levels, enhanced autophagy activity, and attenuated inflammasome activation via downregulation of NLRP3 expression and reducing IL-1β levels. Based on our results, we concluded that ZnO NPs can be considered as a promising agent for slowing the progression of DN via interplay between autophagy and Nrf2/TXNIP/NLRP3 inflammasome signaling.

Epigenetic regulation of TXNIP-mediated oxidative stress and NLRP3 inflammasome activation contributes to SAHH inhibition-aggravated diabetic nephropathy

S-adenosylhomocysteine (SAH) is hydrolyzed by SAH hydrolase (SAHH) to homocysteine and adenosine. Increased plasma SAH levels were associated with disturbed renal function in patients with diabetes. However, the role and mechanism of SAHH in diabetic nephropathy is still unknown. In the present study, we found that inhibition of SAHH by using its inhibitor adenosine dialdehyde (ADA) accumulates intracellular or plasma SAH levels and increases high glucose-induced podocyte injury and aggravates STZ-induced diabetic nephropathy, which is associated with Nod-like receptor protein 3 (NLRP3) inflammasome activation. Inhibition or knockout of NLRP3 attenuates SAHH inhibition-aggravated podocyte injury and diabetic nephropathy. Additionally, SAHH inhibition increases thioredoxin-interacting protein (TXNIP)-mediated oxidative stress and NLRP3 inflammasome activation, but these effects were not observed in TXNIP knockout mice. Mechanistically, SAHH inhibition increased TXNIP by inhibiting histone methyltransferase enhancer of zeste homolog 2 (EZH2) and reduced trimethylation of histone H3 lysine 27 and its enrichment at promoter of early growth response 1 (EGR1). Moreover, EGR1 is activated and enriched at promoters of TXNIP by SAHH inhibition and is essential for SAHH inhibition-induced TXNIP expression. Inhibition of EGR1 protected against SAHH inhibition-induced NLRP3 inflammasome activation and oxidative stress and diabetic nephropathy. Finally, the harmful effects of SAHH inhibition on inflammation and oxidative stress and diabetic nephropathy were also observed in heterozygote SAHH knockout mice. These findings suggest that EZH2/EGR1/TXNIP/NLRP3 signaling cascade contributes to SAHH inhibition-aggravated diabetic nephropathy. Our study firstly provides a novel insight into the role and mechanism of SAHH inhibition in diabetic nephropathy.

Thymoquinone Lowers Blood Glucose and Reduces Oxidative Stress in a Rat Model of Diabetes.

The aim of the present study was to assess the short-term effects of Thymoquinone (TQ) on oxidative stress, glycaemic control, and renal functions in diabetic rats. DM was induced in groups II and III with a single dose of streptozotocin (STZ), while group I received no medication (control). The rats in groups I and II were then given distilled water, while the rats in group III were given TQ at a dose of 50 mg/kg body weight/day for 4 weeks. Lipid peroxidase, nitric oxide (NO), total antioxidant capacity (TAC), glycated haemoglobin (HbA1c), lipid profiles, and renal function were assessed. Moreover, the renal tissues were used for histopathological examination. STZ increased the levels of HbA1c, lipid peroxidase, NO, and creatinine in STZ-induced diabetic rats in comparison to control rats. TAC was lower in STZ-induced diabetic rats than in the control group. Furthermore, rats treated with TQ exhibited significantly lower levels of HbA1c, lipid peroxidase, and NO than did untreated diabetic rats. TAC was higher in diabetic rats treated with TQ than in untreated diabetic rats. The histopathological results showed that treatment with TQ greatly attenuated the effect of STZ-induced diabetic nephropathy. TQ effectively adjusts glycaemic control and reduces oxidative stress in STZ-induced diabetic rats without significant damaging effects on the renal function.

Role of Oxidative Stress and Reduced Endogenous Hydrogen Sulfide in Diabetic Nephropathy.

PurposePersistent hyperglycemia lead towards depletion of hydrogen sulfide (H2S) resulting in generation of oxidative stress and diabetic nephropathy. The aim of the current study was to explore the antioxidant potential of H2S and captopril, a -SH containing compound in streptozotocin (STZ)-induced diabetic nephropathy.MethodsFifty four Wistar-Kyoto (WKY) rats male (200–250g) were divided into nine groups (n=6) with each group injected once with STZ (60mg/kg i.p) except normal control. After 3 weeks of induction of diabetes, groups were assigned as normal control, diabetic control, diabetic-captopril, diabetic-NaHS, diabetic-captopril-NaHS, diabetic-spironolactone, diabetic-metformin, diabetic-metformin-NaHS and diabetic-vitamin-c. All the animals were served with normal saline (N/S 4mL/kg p.o), captopril (50mg/kg/day p.o), sodium hydrosulfide (NaHS) (56µmol/kg i.p), spironolactone (50mg/kg/day s.c), metformin (500mg/kg/day p.o) and vitamin-c (50mg/kg p.o) on daily basis for next 4 weeks, respectively. Metabolic studies, H2S levels, renal hemodynamics and oxidative stress markers were analyzed at 0, 14 and 28 days followed by histopathological analysis of renal tissues.ResultsThe results showed decreased H2S levels, body weight, sodium to potassium ratio, glutathione (GSH), superoxide dismutase (SOD), total antioxidant assay (T-AOC) with malondialdehyde (MDA) and blood glucose levels significantly increased among diabetic rats. Treatment with captopril, NaHS, metformin, spironolactone and vitamin C showed significant improvement among renal hemodynamics and oxidative stress markers, respectively. But treatment groups like NaHS in combination with captopril and metformin showed more pronounced effects.ConclusionThe observations suggest that H2S mediated protective effects on STZ-induced diabetic nephropathy may be associated with reduced oxidative stress via augmenting the antioxidant effect.

Kaempferol attenuates diabetic nephropathy in streptozotocin-induced diabetic rats by a hypoglycaemic effect and concomitant activation of the Nrf-2/Ho-1/antioxidants axis

This study examined the protective effect of Kaempferol against streptozotocin-induced diabetic nephropathy (DN) in rats and studies the underlying mechanisms. Rats were divided into 4 groups as control, control + Kaempferol, STZ, and STZ + Kaempferol. All treatments were conducted for 8 weeks daily after the induction of diabetes. Kaempferol prevented STZ-induced weight and food loss and attenuated renal damage and the alterations in all biochemical related parameters. Concomitantly, Kaempferol reduced renal levels of TNF-α and IL-6, cleaved caspase-3, p38, and Bax, suppressing JNK phosphorylation and NF-κB p65 transactivation, and upregulation of Bcl-2. In both control and STZ-diabetic rats, Kaempferol reduced fasting glucose levels, increased fasting insulin levels and HOMA-β, reduced the levels of ROS and MDA, stimulated SOD and GSH levels, and increased the expression of Nrf2 and HO-1. In conclusion, Kaempferol prevents STZ-induced diabetic nephropathy, mainly, by antioxidant potential, mediated by the upregulation of the Nrf-2/HO-1 axis.

Nephroprotective Effect of Adropinin Against Streptozotocin-Induced Diabetic Nephropathy in Rats: Inflammatory Mechanism and YAP/TAZ Factor.

BackgroundDiabetic Nephropathy remains a major cause of morbidity and mortality in patients suffering from renal dysfunction. This study accessed the nephroprotective role of Adropinin against streptozotocin (STZ) induced diabetic nephropathy in rats and scrutinizes the possible mechanism of action.MethodsSTZ (45 mg/kg) dose was used for inducing diabetic nephropathy (DN) and rats were divided into different groups and received the dose-dependent treatment of Adropinin. Blood glucose level, body weight, tissue weight, antioxidant, renal, hepatic parameters, and cytokines were determined. At the end of the experimental study, renal histopathology was performed.ResultsAdropinin significantly (P<0.001) boosted plasma insulin levels and reduced the blood glucose level. Adropinin considerably increased body weight and reduced kidney weight and kidney hypertrophy. Adropinin significantly (P<0.001) reduced urine outflow, microalbumin, total protein, blood urea nitrogen (BUN), uric acid and increased the creatinine, creatinine clearance. Adropinin significantly (P<0.001) reduced the indole sulfate level in the serum, kidney and reduced in the urine. Adropinin significantly (P<0.001) reduced the total cholesterol, triglyceride, low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL) and increased the level of high-density lipoprotein (HDL). Adropinin significantly (P<0.001) increased the level of antioxidant enzymes such as glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and reduced the level of malonaldehyde (MDA), 8-hydroxy-2ʹ -deoxyguanosine (8-OHdG). Adropinin significantly (P<0.001) reduced the level of interleukin-1β (IL-1β), interleukin-6 (IL-6), transforming growth factor beta (TGF-β) and increased the level of interleukin-10 (IL-10), respectively. Adropinin treatment showed improvement in renal histopathology.ConclusionWe can say that Adropinin showed the nephroprotective effect against the STZ-induced diabetic nephropathy rats via inflammatory and antioxidant pathway.