Knockdown of ChREBP ameliorates retinal microvascular endothelial cell injury and angiogenic responses in diabetic retinopathy.

PURPOSE: To examine whether and how carbohydrate response element-binding protein (ChREBP) plays a role in diabetic retinopathy. METHODS: Western blotting was used to detect ChREBP expression and location following high glucose stimulation of Human Retinal Microvascular Endothelial Cells (HRMECs). Flow cytometry, TUNEL staining, and western blotting were used to evaluate apoptosis following ChREBP siRNA silencing. Cell scratch, transwell migration, and tube formation assays were used to determine cell migration and angiogenesis. Diabetic models for wild-type (WT) and ChREBP knockout (ChKO) mice were developed. Retinas of WT and ChKO animals were cultivated in vitro with vascular endothelial growth factor + high glucose to assess neovascular development. RESULTS: ChREBP gene knockdown inhibited thioredoxin-interacting protein and NOD-like receptor family pyrin domain containing protein 3 expression in HRMECs, which was caused by high glucose stimulation, reduced apoptosis, hindered migration, and tube formation, and repressed AKT/mTOR signaling pathway activation. Compared with WT mice, ChKO mice showed suppressed high glucose-induced alterations in retinal structure, alleviated retinal vascular leakage, and reduced retinal neovascularization. CONCLUSIONS: ChREBP deficiency decreased high glucose-induced apoptosis, migration, and tube formation in HRMECs as well as structural and angiogenic responses in the mouse retina; thus, it is a potential therapeutic target for diabetic retinopathy.

Research on the removal characteristics of surface error with different spatial frequency based on shear thickening polishing method.

X-ray mirrors, which are essential for constructing synchrotron radiation light sources, are highly required for full-range spatial wavelength errors. This paper investigated power-law non-Newtonian fluids and pointed out that both three-body removal and shear removal existed in the shear thickening polishing process. Subsequently, this paper calculates the shear force of the power-law non-Newtonian fluid polishing fluid in polishing the surface with different frequency errors. It establishes an MRR model of shear thickening polishing in the frequency domain by combining it with the Archard equation. Then, this model is also applied to optimize the polishing fluid formulation and processing parameters. Finally, the removal effect of the optimized polishing fluid on the mid-frequency ripple error is experimentally verified. On Ф50 mm monocrystalline silicon, the removal of mid-frequency ripple error with a spatial wavelength of 1 mm was achieved by shear thickening polishing technique while converging the surface roughness to 0.14 nm. Finally, the experimental results were applied to monocrystalline silicon with a length of 500 mm. This work provides a new research idea for the existing shear thickening polishing process. It provides theoretical and technical support for removing the mid- and high-frequency errors in high-precision X-ray mirrors.

Engineering a conformal optical window of a square-to-circular transition isolator.

To realize the flow visualization of shock train structures by Schlieren measurements in a square-to-circular transition isolator, a high-precision conformal optical window was manufactured by fly-cutting technology. According to the light refraction principle, the window's outer surface was iteratively optimized based on the super-elliptic curves of the internal flow channel. Through tolerance analysis and processing parameter optimization, the transmitted wavefront error (RMS value) of the finished window was 0.823λ (λ=632.8n m). Based on a z-type Schlieren apparatus, the high-precision Schlieren measurements were conducted through the window and processed by an image filtering process method. The results promote high-precision Schlieren observation towards square-to-circular transition isolators.

Biomimetic nanochannels for molybdate transport: application to sensitive electrochemical immunoassay for HER2.

A nanochannel-based electrochemical immunoassay was developed for the detection of human epidermal growth factor receptor 2 (HER2), with molybdate as the reporter to explore the interaction occurring into the nanochannels. The presence of target increased steric hindrance of the antibody-functionalized nanochannels, thereby hindering the transport of molybdate. And the reporter could be monitored by working electrode modified with hydroxyapatite nanoparticles, based on the formation of the redox-active molybdophosphate. As a result, peak current obtained at ca. - 0.28 V in square wave voltammograms could be applied to quantitative determination of HER2. The electrochemical signal increased linearly with the logarithm of the concentration of HER2 in a broad dynamic range of 0.1 pg∙mL-1 to 10 ng∙mL-1 with a detection limit of 0.05 pg∙mL-1. The reliability of this immunoassay was validated by a recovery range of 99.5% to 111.7% for the detection of three different levels of HER2 in human serum samples. Integrating with multiple bionanochannels, this immunoassay is expected to provide a versatile approach for quantitative detection of various biomarkers in related disease diagnosis and therapy.

Glis2 inhibits the epithelial-mesenchymal transition and apoptosis of renal tubule cells by regulating the ß-catenin signalling pathway in diabetic kidney disease.

Increasing evidence has supported the idea that epithelial-to-mesenchymal transition (EMT)-based tubulointerstitial fibrosis and the apoptosis of renal tubular epithelial cells (TECs) play important roles in the occurrence and development of Diabetic kidney disease (DKD). Glis2 is abundantly expressed in renal tubules and is a member of the Kruppel-like zinc finger transcription factor family, which is involved in the regulation of normal renal development and function. Glis2 deficiency may be closely associated with tubular atrophy and fibrosis, but the role played by Glis2 in DKD remains unclear. In this study, we found that Glis2 protein expression was downregulated in kidney tissue samples obtained by biopsy from DKD patients as well as HK-2 cells cultured in high-glucose medium, and overexpression of the Glis2 plasmid inhibited the apoptosis and EMT of TECS under HG conditions. In addition, Glis2 overexpression obliterated the activation of the ß-catenin signalling pathway in HG-cultured HK-2 cells. Moreover, the ß-catenin inhibitor XAV939 or XAV939 combined with Glis2 overexpression markedly inhibited the apoptosis and EMT of HG-treated HK-2 cells. All these findings indicated that upregulation of Glis2 expression might attenuate the EMT and apoptosis of renal tubule cells via the ß-catenin signalling pathway under HG conditions. This outcome may lead to a better understanding of the pathogenesis of DKD and provide new insights into prevention and treatment strategies targeting DKD.

Surface Adsorption-Mediated Ultrahigh Efficient Peptide Encapsulation with a Precise Ratiometric Control for Type 1 and 2 Diabetic Therapy.

A surface adsorption strategy is developed to enable the engineering of microcomposites featured with ultrahigh loading capacity and precise ratiometric control of co-encapsulated peptides. In this strategy, peptide molecules (insulin, exenatide, and bivalirudin) are formulated into nanoparticles and their surface is decorated with carrier polymers. This polymer layer blocks the phase transfer of peptide nanoparticles from oil to water and, consequently, realizes ultrahigh peptide loading degree (up to 78.9%). After surface decoration, all three nanoparticles are expected to exhibit the properties of adsorbed polymer materials, which enables the co-encapsulation of insulin, exenatide, and bivalirudin with a precise ratiometric control. After solidification of this adsorbed polymer layer, the release of peptides is synchronously prolonged. With the help of encapsulation, insulin achieves 8 days of glycemic control in type 1 diabetic rats with one single injection. The co-delivery of insulin and exenatide (1:1) efficiently controls the glycemic level in type 2 diabetic rats for 8 days. Weekly administration of insulin and exenatide co-encapsulated microcomposite effectively reduces the weight gain and glycosylated hemoglobin level in type 2 diabetic rats. The surface adsorption strategy sets a new paradigm to improve the pharmacokinetic and pharmacological performance of peptides, especially for the combination of peptides.

Ion beam figuring strategy for aluminum optics with minimal extra material removal.

With the application spectrum moving from infrared to visible light, aluminum optics with complex forms are difficult to fabricate by the majority of existing processing methods. Possessing the highest machining precision and low processing contamination, ion beam figuring (IBF) is a better method for fabrication of aluminum optics. However, the surface roughness deteriorates with the removal depth during IBF. In this study, the extra material removal during the IBF process is studied systematically. Extra material removal consists of two parts, determined by the convolution process and the limitation of the dynamic performance of machining tools. Extra material removal can be reduced by filtering out the surface residual error with a spatial frequency higher than the cut-off frequency and reducing the iterations of the machining process. Then, the executability of the dwell time matrix and the figuring ability of the removal function are analyzed. Adjusting the working parameters (volume removal rate) reduces the requirements for dynamic performance of machining tools. Finally, a minimal material removal processing strategy for aluminum optics based on power spectral density analysis and a spatial frequency filtering method is proposed. A simulation is conducted to verify the feasibility of the proposed strategy. With the same final precision (59.8 nm PV and 4.4 nm RMS), the maximum material removal decreases nearly 36 nm by applying the strategy, which reduces roughness nearly 10 nm. This study promotes the application of IBF in the field of aluminum optics fabrication as well as improves the machining precision of aluminum optics.

Integrative design and processing of a conformal optical window pair in a cylindrical isolator.

In order to perform the flow visualization of a shock train structure by the schlieren imaging method in the cylindrical isolator, to the best of our knowledge, a novel integrative design and processing scheme of an aluminum alloy pipe with an acrylic conformal optical window pair are proposed. The optical ray tracing and wavefront correction methods were applied to design the inner cylindrical surfaces and outer aspherical cylindrical surfaces of the optical window pair for parallel light correction based on the conjoint analysis with the processing capability. Under the tolerance analysis and the optimization of the machining path, the integrative model was fabricated on a three-axis computer numerical control machine using two-axis turning and fast tool servo machining. The wavefront aberration (peak-to-valley value) and wavefront aberration (RMS) of the optical window pair were corrected within 12.189 and 2.658λ (λ=632.8nm) in the observation area which met the requirements of high-precision schlieren observation.

Co-delivery of F7 and crizotinib by thermosensitive liposome for breast cancer treatment.

In order to enhance the targeting efficiency and reduce the side effects and drug resistance, crizotinib (Cri) and F7 were co-loaded in a thermosensitive liposome (TSL) (F7-Cri-TSL), which showed enhanced permeability and retention in breast cancer model, as well as local controlled release by external hyperthermia. Cri is an inhibitor for cell proliferation and a promoter of apoptosis, by inhibiting the phosphorylation of intracellular ALK and c-Met, but its drug resistance limits its application. F7 is a novel drug candidate with significant resistance to cyclin-dependent kinase, but its use was restricted by its high toxicity. The F7-Cri-TSL was found with excellent particle size (about 108 nm), high entrapment efficiency (>95%), significant thermosensitive property, and good stability. Furthermore, F7-Cri-TSL/H had strongest cell lethality compared with other formulations. On the MCF-7 xenograft mice model, the F7-Cri-TSL also exhibited therapeutic synergism of Cri, F7 and hyperthermia. Meanwhile, it was shown that the TSL reduced the systemic toxicity of the chemotherapy drug. Therefore, the F7-Cri-TSL may serve as a promising system for temperature triggered breast cancer treatment.

Carbohydrate response element-binding protein regulates lipid metabolism via mTOR complex1 in diabetic nephropathy.

Lipid deposition caused by the disorder of renal lipid metabolism is involved in diabetic nephropathy (DN). Carbohydrate response element-binding protein (ChREBP) is a key transcription factor in high glucose-induced cellular fat synthesis. At present, the regulation and mechanism of ChREBP on fat metabolism in diabetic kidneys are still unclear. In this study, we showed that lack of ChREBP significantly improved renal injury, inhibited oxidative stress, lipid deposition, fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC) and thioredoxin-interacting protein (TXNIP) expression, as well as the activity of mammalian target of rapamycin complex 1 (mTORC1) in diabetic kidneys. Meanwhile, ChREBP deficiency upregulated the expression of peroxisome proliferator-activated receptor-α (PPARα), carnitine palmitoyltransferaser 1A (CPT1A) and acyl-coenzyme A oxidase 1 (ACOX1) in diabetic kidneys. In vitro, knockdown of ChREBP attenuated lipid deposition, mTORC1 activation, and expression of FASN and ACC, increased PPARα, CPT1A, and ACOX1 expression in HK-2 cells and podocytes under high glucose (HG) conditions. Moreover, HG-induced lipid deposition, increased expression of FASN and ACC and decreased expression of PPARα, CPT1A, and ACOX1 were reversed by rapamycin, a specific inhibitor of mTORC1, in HK-2 cells. These results indicate that ChREBP deficiency alleviates diabetes-associated renal lipid accumulation by inhibiting mTORC1 activity and suggest that reduction of ChREBP is a potential therapeutic strategy to treat DN.

High efficiency removal of single point diamond turning marks on aluminum surface by combination of ion beam sputtering and smoothing polishing.

Single point diamond turning (SPDT) is highly versatile in fabricating axially symmetric form, non-axially-symmetric form and free form surfaces. However, inevitable microstructure known as turning marks left on the surface have limited the mirror's optical performance. Based on chemical mechanical polishing (CMP) mechanism, smoothing polishing (SP) process is believed to be an effective method to remove turning marks. However, the removal efficiency is relatively low. In this paper, based on Greenwood-Williamson (GW) theory, the factors that limit removal efficiency of SP are discussed in details. Influences of process parameters (work pressure and rotational speed) are firstly discussed. With further analysis, surface spectral characteristics are identified as the inherent factor affecting further efficiency improvement. According to theoretical analysis, the removal efficiency of isotropic surface is nearly 1.8 times higher than anisotropy surface like surface with turning marks. A high efficiency turning marks removal process combining ion beam sputtering (IBS) and SP is proposed in our research. With removal depth exceeding 100 nm, the isotropic aluminum surface can be constructed by IBS so that the efficiency of SP process can be greatly improved. Though deteriorated by IBS, the surface roughness will be rapidly reduced by SP process. Finally, experiments are conducted to verify our analysis. A 3.7 nm roughness surface without turning marks is achieved by new method while direct SP can only reach roughness of 4.3 nm with evident turning marks. Experimental results show that removal efficiency nearly doubled which matches well with the theoretical analysis. Our research not only can be used as a high efficiency turning marks removal and surface quality improvement method but also can be a new method for high precision aluminum optics fabrication.

Rapid fabrication technique for aluminum optics by inducing a MRF contamination layer modification with Ar+ ion beam sputtering.

Aluminum optics are widely used in modern optical systems because of high specific stiffness and high reflectance. Magnetorheological finishing (MRF) provides a highly deterministic technology for high precision aluminum optics fabrication. However, the contamination layer will generate on the surface and bring difficulties for the subsequent processes, which highly limit the fabrication efficiency and precision. In this study, characteristics of the contamination layer and its formation process are firstly revealed through experimental and theoretical methods. Impurities such as abrasives are embedded into the aluminum substrate causing increasing surface hardness. The influence of the contaminant layer on machining accuracy and machining efficiency is analyzed in this study. Based on the analysis, ion beam sputtering (IBS) is induced as a contamination layer modification method. Impurities will be preferential sputtered during the process. Surface hardness and brightness will restore to the state before MRF. Moreover, the thickness of the contamination layer reduces dynamically during IBS because of the bombardment-induced Gibbsian segregation and sputter yield amplification mechanism. Consequently, we proposed a combined technique that includes MRF, IBS and smoothing polishing. Comparative experiments are performed on an elliptical shape plane surface. The results indicate that the efficiency has been increased sevenfold and surface precision is also highly improved. Our research will promote the application of aluminum optics to the visible and even ultraviolet band.

High precision fabrication of aluminum optics by optimizing an Ar+ ion beam figuring strategy for polishing the contamination layer.

Benefiting from high specific stiffness and high reflectance, aluminum optics with a complex surface profile are widely used in aerospace optical systems which have strict requirements for volume of the systems. Contact figuring polishing process provides highly deterministic technology for the fabrication of high precision aluminum optics. However, due to the high chemical activity of aluminum, the inevitable contamination layer will generate on the surface and bring difficulties for the subsequent processes, which greatly limit the fabrication precision. Ion beam figuring (IBF) is an effectively technology that can remove the contamination layer and improve surface quality. But, the surface profile may deteriorate during IBF. In this study, through experimental method, the nonuniformity of the contamination layer is found to be the inducer for deterioration and deviation of surface profile during IBF. The mapping between the characteristics of contamination layer and dwell time of contact polishing is studied. The thickness of the contamination layer will firstly increase with dwell time and stabilize to 120 nm when the dwell time exceeds a specific value. The variation of the IBF removal function with removal depth is also revealed through experimental and theoretical methods. Due to the dynamic variation of the composition in the contamination layer during IBF, the removal function increases with the removal depth and stabilizes when the depth exceeds 60 nm (the contamination layer is fully removed). Consequently, we propose two processing strategies to improve the aluminum optics fabrication process. Comparative experiments are performed on two off-axis aspherical surfaces. The results indicate that the surface profile can be stably maintained and improved during IBF processing based on the proposed strategies. Our research will significantly improve the fabrication precision of aluminum optics and promote the application of aluminum optics to the visible and even ultraviolet band.

Surface roughness evolution mechanism of the optical aluminum 6061 alloy during low energy Ar+ ion beam sputtering.

Ultra-smooth surfaces with low contamination and little damage are a great challenge for aluminum optical fabrication. Ion beam sputtering (IBS) has obvious advantages of low contamination and non-contact that make it a perfect method for processing aluminum optics. However, the evolution laws of aluminum surface morphology are quite different from conventional amorphous materials, which affects the roughness change and needs systematic research. Thus, in this paper, the roughness evolution of an aluminum optical surface (i.e., aluminum mirror) subjected to IBS has been studied with experimental and theoretical methods. The surface morphology evolution mechanisms of turning marks and second phase during IBS are revealed. The newly emerging relief morphology and its evolution mechanism are studied in depth. The experimental results find that IBS causes the coarsening of optical surfaces and the appearance of microstructures, leading to the surface quality deterioration. Turning marks have been through the process of deepening and vanish, while second phase generates microstructures on the original surface. The corresponding mechanism is discussed exhaustively. Preferential sputtering, curvature-dependent sputtering and material properties play important roles on surface quality deterioration. A modified roughness evolution mechanism and an improved binary sputtering theory are proposed to describe the polycrystalline sputtering phenomena. The current research can provide a guidance for the application of IBS in aluminum optics manufacture fields.

Resveratrol Reduces Oxidative Stress and Apoptosis in Podocytes via Sir2-Related Enzymes, Sirtuins1 (SIRT1)/Peroxisome Proliferator-Activated Receptor γ Co-Activator 1α (PGC-1α) Axis.

BACKGROUND PGC-1α can be activated by deacetylation reactions catalyzed by SIRT1. Resveratrol is currently known as a potent activator of SIRT1. However, it is unknown whether the renal-protective effect of resveratrol is further related to activation of the podocyte SIRT1/PGC-1α pathway. MATERIAL AND METHODS High glucose was used to stimulate mouse podocytes. Resveratrol and PGC-1α siRNA transfection were used to perform co-intervention treatments. The protein and mRNA expression levels of SIRT1, PGC-1α, NRF1, and TFAM were detect by immunofluorescence, Western blot analysis, and qRT-PCR in the podocytes, respectively. DCHF-DA and MitoSOX™ staining were used to monitor the total ROS and mitochondrial ROS levels, respectively. The specific activities of complexes I and III were measured using Complex I and III Assay Kits. Mitochondrial membrane potential and cell apoptosis were measured using JC-1 staining and Annexin V-FITC/PI double-staining, respectively. RESULTS We found that high-glucose stimulation results in time-dependent decreases in the expression of SIRT1, PGC-1α, and its downstream genes NRF1 and mitochondrial transcription factor A (TFAM) for mouse podocytes, and increases ROS levels in cells and mitochondria. Moreover, the expression of nephrin was downregulated and the cell apoptotic rate was increased. Resveratrol treatment can improve abnormalities caused by high-glucose stimulation. In addition, it can also reduce the release of mitochondrial cytochrome C and DIABLO proteins to the cytoplasm and increase respiratory chain complex I and III activity and mitochondrial membrane potential. CONCLUSIONS Resveratrol can reduce the oxidative damage and apoptosis of podocytes induced by high-glucose stimulation via SIRT1/PGC-1α-mediated mitochondrial protection.

Study on the surface crystallization mechanism and inhibition method in the CMP process of aluminum alloy mirrors.

Owing to its material properties, aluminum-based optical loads are widely used in the aerospace field. At present, the main processing of an aluminum alloy mirror is single-point diamond turning followed by the combined polishing process. The surface will generate some white crystals during the chemical mechanical polishing process (CMP). These crystals can affect the improvement of surface quality and seriously reduce the processing efficiency of the whole process. In view of the above problems, four main factors of crystallization are obtained by interface theoretical analysis, Visual MINTEQ simulation of chemical morphological distribution, and experimental analysis. They are temperature, PH value of polishing fluid, solid-liquid contact angle, and impurity content of aluminum alloy. The crystallization phenomenon in the polishing process is successfully suppressed by improving the polishing process and selecting new materials. The experimental results showed that the surface roughness decreased from 7.21 to 2.98 nm without crystallization using the new method.

Protease-activated receptor-2 promotes kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway.

Protease-activated receptor-2 (PAR2), which belongs to a specific class of the G-protein-coupled receptors, is central to several inflammation processes. However, the precise molecular mechanism involved remains undefined. Autophagy has been previously shown to affect inflammation. In the present study, we examine the effect of PAR2 on kidney tubular epithelial autophagy and on autophagy-related inflammation and reveal the underlying mechanism involved. Autophagic activity and levels of autophagic marker LC3 were examined in human kidney tubular epithelial cells with PAR2 knockdown or overexpression. We administered the mammalian target of rapamycin (mTOR) inhibitor (rapamycin) or activator (MHY1485) to investigate the function of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway. We also used transforming growth factor-ß1 (TGF-ß1)-induced HK-2 cell inflammation models to investigate the role of PAR2-associated autophagy in kidney tubular epithelial inflammation. PAR2 antagonist and rapamycin were administered to mice after unilateral ureteral obstruction to detect the correlations between PAR2, autophagy, and inflammation. Our results show that PAR2 overexpression in HK-2 cells led to a greater reduction in autophagy via the PI3K/Akt/mTOR pathway activation and induces autophagy-related inflammation. Meanwhile, a knockdown of PAR2 via PAR2 RNAi transfection greatly increased autophagy and alleviated autophagy-associated inflammation. In unilateral ureteral obstruction (UUO) kidneys, PAR2 antagonist treatment greatly attenuated renal inflammation and interstitial injury by enhancing autophagy. Moreover, inhibition of mTOR, rapa, markedly increased autophagy and inhibited the UUO-induced inflammation. We conclude that PAR2 induces kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway. Our results are suggestive that PAR2 inhibition may play a role in the treatment of diseases with increased inflammatory responses in renal systems.

Inhibition of Necroptosis Attenuates Kidney Inflammation and Interstitial Fibrosis Induced By Unilateral Ureteral Obstruction.

BACKGROUND: Inflammation plays a crucial role in renal interstitial fibrosis, the pathway of chronic kidney diseases. Necroptosis is a novel form of regulated cell death, which plays a potential role in inflammation and renal diseases. The small molecule necrostatin-1 (Nec-1) is a specific inhibitor of necroptosis. This study was aimed at determining the role of necroptosis, RIP1/RIP3/mixed lineage kinase domain-like (MLKL) signaling pathway, in renal inflammation and interstitial fibrosis related to primitive tubulointerstitial injury. It was also aimed at evaluating the effect of Nec-1 in renal fibrosis induced by unilateral ureteral obstruction (UUO). METHODS: Renal histology, immunohistochemistry, western blot, and real-time polymerase chain reaction were performed using UUO C57BL/6J mice model. Moreover, we tested whether Nec-1 was renal-protective in the interstitial fibrosis kidney. Mice were exposed to UUO and injected intraperitoneal with Nec-1 or vehicle. RESULTS: The levels of RIP1/RIP3/MLKL protein and mRNA were increased in the obstructed kidneys 7 days after UUO; this was accompanied by changes in renal pathological lesions. Renal histological examination showed lesser renal damage in Nec-1-treated UUO mice. Renal inflammation, assessed by tumor necrosis factor-α, interleukin-1ß, and monocyte chemotactic protein-1 was markedly attenuated by Nec-1. Furthermore, Nec-1 treatment also significantly reduced TGF-ß and α-smooth muscle actin, indicating lesser renal interstitial fibrosis. CONCLUSION: These findings suggest that the participation of necroptosis in UUO is partly demonstrated. And necroptosis inhibition may have a potential role in the treatment of diseases with increased inflammatory response and interstitial fibrosis in renal.

Mitochondria-targeted peptide SS-31 attenuates renal injury via an antioxidant effect in diabetic nephropathy.

Oxidative stress is implicated in the pathogenesis of diabetic kidney injury. SS-31 is a mitochondria-targeted tetrapeptide that can scavenge reactive oxygen species (ROS). Here, we investigated the effect and molecular mechanism of mitochondria-targeted antioxidant peptide SS-31 on injuries in diabetic kidneys and mouse mesangial cells (MMCs) exposed to high-glucose (HG) ambience. CD-1 mice underwent uninephrectomy and streptozotocin treatment prior to receiving daily intraperitoneal injection of SS-31 for 8 wk. The diabetic mice treated with SS-31 had alleviated proteinuria, urinary 8-hydroxy-2-deoxyguanosine level, glomerular hypertrophy, and accumulation of renal fibronectin and collagen IV. SS-31 attenuated renal cell apoptosis and expression of Bax and reversed the expression of Bcl-2 in diabetic mice kidneys. Furthermore, SS-31 inhibited expression of transforming-growth factor (TGF)-ß1, Nox4, and thioredoxin-interacting protein (TXNIP), as well as activation of p38 MAPK and CREB and NADPH oxidase activity in diabetic kidneys. In vitro experiments using MMCs revealed that SS-31 inhibited HG-mediated ROS generation, apoptosis, expression of cleaved caspase-3, Bax/Bcl-2 ratio, and cytochrome c (cyt c) release from mitochondria. SS-31 normalized mitochondrial potential (ΔΨm) and ATP alterations, and inhibited the expression of TGF-ß1, Nox4, and TXNIP, as well as activation of p38 MAPK and CREB and NADPH oxidase activity in MMCs under HG conditions. SS-31 treatment also could reverse the reduction of thioredoxin (TRX) biologic activity and upregulate expression of thioredoxin 2 (TRX2) in MMCs under HG conditions. In conclusion, this study demonstrates a protective effect of SS-31 against HG-induced renal injury via an antioxidant mechanism in diabetic nephropathy.