scholarly journals Mir-138 plays an important role in diabetic nephropathy through SIRT1-p38-TTP regulatory axis

2020 ◽  
Author(s):  
Fengxun Liu ◽  
Jia Guo ◽  
Yingjin Qiao ◽  
Shaokang Pan ◽  
Jiayu Duan ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Nephropathy ◽  
Experimental Methods ◽  
Therapeutic Effects ◽  
Key Factors ◽  
Regulatory Relationship ◽  
Podocyte Injury ◽  
P38 Pathway

Abstract Background : Diabetic nephropathy (DN) is the main cause of chronic kidney disease (CKD) and is one of the most common and serious complications of diabetes mellitus (DM). SIRT1 and TTP are two important protective factors in DN, however, the regulatory relationship between SIRT1 and TTP and the underneath mechanism are interesting but still unclear. Identifying the key factors that regulate SIRT1 or TTP may be of great value to the understanding and treatment of the DN. Methods : in this study, through systematic experimental methods, we found that the expression of miR-138 was significantly up-regulated in DN clinical patients samples, and our experimental results suggested that miR-138 could bind the 3’UTR of SIRT1 and inhibit its expression in both cultured podocytes and db/db mice kidney tissues. Results : furthermore, our in vitro and in vivo date also indicated miR-138 could target SIRT1 and affect TTP through p38 pathway. And down-regulation of miR-138 attenuated podocyte injury and showed some extend of therapeutic effects in DN mice models. Conclusion : our findings reveal that the regulatory axis of miR-138-SIRT1-p38-TTP might play a key role in DN. We believe these findings may be of some value for deepening the understanding of DN and may serve as a reference for future treatment of this disease.

scholarly journals Ginsenoside Rg1 Alleviates Podocyte Injury Induced by Hyperlipidemia via Targeting the mTOR/NF-κB/NLRP3 Axis

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Tao Wang ◽  
Yanbin Gao ◽  
Rongchuan Yue ◽  
Xiaolei Wang ◽  
Yimin Shi ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Diabetic Rats ◽  
Therapeutic Effects ◽  
Ginsenoside Rg1 ◽  
Podocyte Injury ◽  
Therapeutic Function ◽  
Polymerase Chain ◽  
Underlying Mechanisms

Background. Podocyte injury plays an important role in diabetic nephropathy (DN). The aim of this study was to determine the potential therapeutic effects of the ginsenoside Rg1 on hyperlipidemia-stressed podocytes and elucidate the underlying mechanisms. Methods. In vitro and in vivo models of DN were established as previously described, and the expression levels of relevant markers were analyzed by Western blotting, real-time Polymerase Chain Reaction (PCR), immunofluorescence, and immunohistochemistry. Results. Ginsenoside Rg1 alleviated pyroptosis in podocytes cultured under hyperlipidemic conditions, as well as in the renal tissues of diabetic rats, and downregulated the mammalian target of rapamycin (mTOR)/NF-κB pathway. In addition, Rg1 also inhibited hyperlipidemia-induced NLRP3 inflammasome in the podocytes, which was abrogated by the mTOR activator L-leucine (LEU). The antipyroptotic effects of Rg1 manifested as improved renal function in the DN rats. Conclusion. Ginsenoside Rg1 protects podocytes from hyperlipidemia-induced damage by inhibiting pyroptosis through the mTOR/NF-κB/NLRP3 axis, indicating a potential therapeutic function in DN.

Investigation of the anti-diabetic nephropathy activity of puerarin

2020 ◽  
Vol 10 (11) ◽  
pp. 1846-1853
Author(s):  
Wen-Feng Zhang ◽  
Yan Yang ◽  
Xin Li ◽  
Bo Yang ◽  
Pei-Yu He ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Collagen Type Iv ◽  
Therapeutic Effects ◽  
Type Iv ◽  
Enzymelinked Immunosorbent Assay ◽  
Hematoxylin And Eosin

Puerarin has potential therapeutic effects on diabetic nephropathy (DN), but the effectiveness as a treatment for DN and the underlying mechanism remain to be elucidated. The DN-like model induced by high glucose in vitro and the DN model induced by streptozotocin in vivo were used to observe the effect of puerarin. The results showed that puerarin can enhance the activity of HBZY-1 cells and reduce apoptosis. in vivo enzymelinked immunosorbent assay and biochemical assay showed that puerarin can improve DN symptoms. Using hematoxylin and eosin staining to stain kidney tissues confirmed that puerarin has a protective effect on DN. Furthermore, puerarin can reduce the content of collagen type IV, laminin LN, tumor necrosis factor, p38, CREB, Fos, Jun, and MMP9 in HBZY-1 cells and DN rats. In conclusion, puerarin can effectively prevent apoptosis in vitro and improve DN-like symptoms by inhibiting the p38/MAPK signaling pathway in vivo. Therefore, puerarin has the potential to treat DN.

scholarly journals METTL14 aggravates podocyte injury and glomerulopathy progression through N6-methyladenosine-dependent downregulating of Sirt1

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Zhihui Lu ◽  
Hong Liu ◽  
Nana Song ◽  
Yiran Liang ◽  
Jiaming Zhu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Posttranscriptional Regulation ◽  
Kidney Diseases ◽  
Luciferase Reporter ◽  
Podocyte Injury ◽  
Glomerular Function ◽  
Apoptosis And Inflammation ◽  
Dual Luciferase Reporter Assay

AbstractPodocytes are known to play a determining role in the progression of proteinuric kidney disease. N6-methyladenosine (m6A), as the most abundant chemical modification in eukaryotic mRNA, has been reported to participate in various pathological processes. However, its role in podocyte injury remains unclear. In this study, we observed the elevated m6A RNA levels and the most upregulated METTL14 expression in kidneys of mice with adriamycin (ADR) and diabetic nephropathy. METTL14 was also evidently increased in renal biopsy samples from patients with focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy and in cultured human podocytes with ADR or advanced glycation end product (AGE) treatment in vitro. Functionally, we generated mice with podocyte-specific METTL14 deletion, and identified METTL14 knockout in podocytes improved glomerular function and alleviated podocyte injury, characterized by activation of autophagy and inhibition of apoptosis and inflammation, in mice with ADR nephropathy. Similar to the results in vivo, knockdown of METTL14 facilitated autophagy and alleviated apoptosis and inflammation in podocytes under ADR or AGE condition in vitro. Mechanically, we identified METTL14 knockdown upregulated the level of Sirt1, a well-known protective deacetylase in proteinuric kidney diseases, in podocytes with ADR or AGE treatment. The results of MeRIP-qPCR and dual-luciferase reporter assay indicated METTL14 promoted Sirt1 mRNA m6A modification and degradation in injured podocytes. Our findings suggest METTL14-dependent RNA m6A modification contributes to podocyte injury through posttranscriptional regulation of Sirt1 mRNA, which provide a potential approach for the diagnosis and treatment of podocytopathies.

scholarly journals Antioxidative Property and Molecular Mechanisms Underlying Geniposide-Mediated Therapeutic Effects in Diabetes Mellitus and Cardiovascular Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-20 ◽  
Author(s):  
Ning Li ◽  
Ling Li ◽  
Haiming Wu ◽  
Heng Zhou
Keyword(s):  
Diabetes Mellitus ◽  
Cardiovascular Disease ◽  
Molecular Mechanisms ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Iridoid Glucoside ◽  
Gardenia Jasminoides ◽  
Antioxidative Property

Geniposide, an iridoid glucoside, is a major component in the fruit of Gardenia jasminoides Ellis (Gardenia fruits). Geniposide has been experimentally proved to possess multiple pharmacological actions involving antioxidative stress, anti-inflammatory, antiapoptosis, antiangiogenesis, antiendoplasmic reticulum stress (ERS), etc. In vitro and in vivo studies have further identified the value of geniposide in a spectrum of preclinical models of diabetes mellitus (DM) and cardiovascular disorders. The antioxidative property of geniposide should be attributed to the result of either the inhibition of numerous pathological processes or the activation of various proteins associated with cell survival or a combination of both. In this review, we will summarize the available knowledge on the antioxidative property and protective effects of geniposide in DM and cardiovascular disease in the literature and discuss antioxidant mechanisms as well as its potential applications in clinic.

P0989VDR/ATG3 AXIS REGULATES SLIT DIAGRAM TO TIGHT JUNCTION TRANSITION VIA P62-MEDIATED AUTOPHAGY PATHWAY IN DIABETIC NEPHROPATHY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Jingyi Qian ◽  
Bin Wang ◽  
Bicheng Liu
Keyword(s):  
Diabetic Nephropathy ◽  
Tight Junction ◽  
Degradation Pathway ◽  
Serum Starvation ◽  
Autophagic Flux ◽  
Vdr Gene ◽  
Podocyte Injury ◽  
Autophagy Pathway

Abstract Background and Aims Vitamin D receptor (VDR) loss, slit diagram (SD) to tight junction (TJ) transition and impaired autophagic flux contribute to podocyte injury in diabetic nephrology. This study aims to examine the effect and mechanism of VDR on autophagic flux and SD-TJ transition in diabetic nephropathy. Method Renal biopsy tissues from DN patients at stage IIa, IIb, III, IV and patients with minimal lesions were used to evaluate the expression of VDR, autophagic flux and SD-TJ transition glomeruli. In vitro, cultured podocytes were treated with serum starvation (SS), autophagic inhibitors (3-methyladenine 3-MA or chloroquine CQ) to determine the degradation pathway of TJ marker ZO-1. Meanwhile, db/db mice and STZ-induced rats were used to explore the therapeutic effect and mechanism of VDR agonist in diabetic nephropathy. Results SD-TJ transition between foot processes could be observed under electron microscopy in DN patients at all stages, whereas foot processes were separated by the filtration slit and appeared to be single cross-strands in the normal glomeruli. There was a trend of increasing expression of autophagic marker p62 and ZO-1 and the expression of p62 is positively correlated with the changes of ZO-1 in the glomeruli of DN patients. In vitro, inhibiting autophagy with 3-MA and CQ resulted in the accumulation of ZO-1 in cultured podocytes. In addition, Co-IP experiments further convinced the interaction between p62 and ZO-1, which was enhanced by the activation of autophagy. Podocytes apoptosis and the activity of caspase 3 and caspase 8 were significantly increased in the presence of 3-MA or CQ, while these effects were rescued by silencing p62. According to VDR gene expression data in GEO database, VDR expression was decreased in diabetic nephropathy patients compared with normal people. Knocking down VDR lowered the expression of atg3 and leaded to the blockage of autophagy, which could be reversed by over-expressing Atg3. Podocytes treated with high glucose resulted in the decrease of VDR and Atg3, impaired autophagic flux and aggravated podocytes injury. However, VDR agonist treatment partially reversed all the changes. In vivo, db/db mice and STZ-induced rats (DN animal models) exhibited SD-TJ transition, massive proteinuria, decreased expression of VDR and podocin and the increased accumulation of p62 and ZO-1, all of which could be partially reversed by VDR agonist. Conclusion VDR loss contributed to the impairment of autophagic flux and SD-TJ transition via down-regulation Atg3 in diabetic nephropathy. Here, we identified a new mechanism and evidence for VDR agonist to treat diabetic nephropathy.

scholarly journals Curcumin Protects Against Cognitive Impairments in a Rat Model of Chronic Cerebral Hypoperfusion Combined with Diabetes Mellitus by Suppressing Neuroinflammation, Apoptosis, and Pyroptosis

2020 ◽  
Author(s):  
Yaling Zheng ◽  
Jiawei Zhang ◽  
Yao Zhao ◽  
Yaxuan Zhang ◽  
Xiaojie Zhang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Cognitive Impairments ◽  
Neuronal Cell ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Receptor Protein ◽  
Therapeutic Effects ◽  
Protective Effects

Abstract BackgroundChronic cerebral hypoperfusion (CCH) is regarded as a high-risk factor for cognitive decline in vascular dementia (VaD). We have previously shown that diabetes mellitus (DM) synergistically promotes CCH-induced cognitive dysfunction via exacerbating neuroinflammation. Furthermore, curcumin has been shown to exhibit anti-inflammatory and neuroprotective activities. However, the effects of curcumin on CCH-induced cognitive impairments in DM have remained unknown.MethodsRats were fed with a high-fat diet (HFD) and injected with low-dose streptozotocin (STZ), followed by bilateral common carotid artery occlusion (BCCAO), to model DM and CCH in vivo. After BCCAO, curcumin (50 mg/kg) was administered intraperitoneally every two days for eight weeks to evaluate its therapeutic effects. Additionally, mouse BV2 microglial cells were exposed to hypoxia and high glucose to model CCH and DM pathologies in vitro. ResultsCurcumin treatment significantly improved DM/CCH-induced cognitive deficits and attenuated neuronal cell death. Molecular analysis revealed that curcumin exerted protective effects via suppressing neuroinflammation induced by microglial activation, regulating the triggering receptor expressed on myeloid cells 2 (TREM2)/toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway, alleviating apoptosis, and reducing nod-like receptor protein 3 (NLRP3)-dependent pyroptosis.ConclusionsTaken together, our findings suggest that curcumin represents a promising therapy for DM/CCH-induced cognitive impairments.

scholarly journals Platelet-Derived Biomaterials Exert Chondroprotective and Chondroregenerative Effects on Diabetes Mellitus-Induced Intervertebral Disc Degeneration

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1054
Author(s):  
Wen-Cheng Lo ◽  
Chun-Chao Chang ◽  
Chun-Hao Chan ◽  
Abhinay Kumar Singh ◽  
Yue-Hua Deng ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Growth Factor ◽  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Transforming Growth Factor ◽  
Disc Height ◽  
Therapeutic Effects

Complications of diabetes mellitus (DM) range from acute to chronic conditions, leading to multiorgan disorders such as nephropathy, retinopathy, and neuropathy. However, little is known about the influence of DM on intervertebral disc degeneration (IVDD). Moreover, traditional surgical outcomes in DM patients have been found poor, and to date, no definitive alternative treatment exists for DM-induced IVDD. Recently, among various novel approaches in regenerative medicine, the concentrated platelet-derived biomaterials (PDB), which is comprised of transforming growth factor-β1 (TGF-β1), platelet-derived growth factor (PDGF), etc., have been reported as safe, biocompatible, and efficacious alternatives for various disorders. Therefore, we initially investigated the correlations between DM and IVDD, through establishing in vitro and in vivo DM models, and further evaluated the therapeutic effects of PDB in this comorbid pathology. In vitro model was established by culturing immortalized human nucleus pulposus cells (ihNPs) in high-glucose medium, whereas in vivo DM model was developed by administering streptozotocin, nicotinamide and high-fat diet to the mice. Our results revealed that DM deteriorates both ihNPs and IVD tissues, by elevating reactive oxygen species (ROS)-induced oxidative stress, inhibiting chondrogenic markers and disc height. Contrarily, PDB ameliorated IVDD by restoring cellular growth, chondrogenic markers and disc height, possibly through suppressing ROS levels. These data imply that PDB may serve as a potential chondroprotective and chondroregenerative candidate for DM-induced IVDD.

scholarly journals The antioxidant silybin prevents high glucose-induced oxidative stress and podocyte injury in vitro and in vivo

2013 ◽  
Vol 305 (5) ◽  
pp. F691-F700 ◽  
Author(s):  
Khaled Khazim ◽  
Yves Gorin ◽  
Rita Cassia Cavaglieri ◽  
Hanna E. Abboud ◽  
Paolo Fanti
Keyword(s):  
Diabetic Nephropathy ◽  
Nadph Oxidase ◽  
High Glucose ◽  
Drop Out ◽  
Superoxide Production ◽  
Kidney Cortex ◽  
Active Constituent ◽  
Podocyte Injury

Podocyte injury, a major contributor to the pathogenesis of diabetic nephropathy, is caused at least in part by the excessive generation of reactive oxygen species (ROS). Overproduction of superoxide by the NADPH oxidase isoform Nox4 plays an important role in podocyte injury. The plant extract silymarin is attributed antioxidant and antiproteinuric effects in humans and in animal models of diabetic nephropathy. We investigated the effect of silybin, the active constituent of silymarin, in cultures of mouse podocytes and in the OVE26 mouse, a model of type 1 diabetes mellitus and diabetic nephropathy. Exposure of podocytes to high glucose (HG) increased 60% the intracellular superoxide production, 90% the NADPH oxidase activity, 100% the Nox4 expression, and 150% the number of apoptotic cells, effects that were completely blocked by 10 μM silybin. These in vitro observations were confirmed by similar in vivo findings. The kidney cortex of vehicle-treated control OVE26 mice displayed greater Nox4 expression and twice as much superoxide production than cortex of silybin-treated mice. The glomeruli of control OVE26 mice displayed 35% podocyte drop out that was not present in the silybin-treated mice. Finally, the OVE26 mice experienced 54% more pronounced albuminuria than the silybin-treated animals. In conclusion, this study demonstrates a protective effect of silybin against HG-induced podocyte injury and extends this finding to an animal model of diabetic nephropathy.

scholarly journals The Potential Roles of Artemisinin and Its Derivatives in the Treatment of Type 2 Diabetes Mellitus

2020 ◽  
Vol 11 ◽  
Author(s):  
Ya-yi Jiang ◽  
Jia-cheng Shui ◽  
Bo-xun Zhang ◽  
Jia-wei Chin ◽  
Ren-song Yue
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Cell Function ◽  
Public Health Problem ◽  
Therapeutic Effects ◽  
Global Public Health

Type 2 diabetes mellitus (T2DM) is a chronic disease that has become a global public health problem. Studies on T2DM prevention and treatment mostly focus on discovering therapeutic drugs. Artemisinin and its derivatives were originally used as antimalarial treatments. In recent years, the roles of artemisinins in T2DM have attracted much attention. Artemisinin treatments not only attenuate insulin resistance and restore islet ß-cell function in T2DM but also have potential therapeutic effects on diabetic complications, including diabetic kidney disease, cognitive impairment, diabetic retinopathy, and diabetic cardiovascular disease. Many in vitro and in vivo experiments have confirmed the therapeutic utility of artemisinin and its derivatives on T2DM, but no article has systematically demonstrated the specific role artemisinin plays in the treatment of T2DM. This review summarizes the potential therapeutic effects and mechanism of artemisinin and its derivatives in T2DM and associated complications, providing a reference for subsequent related research.

scholarly journals Effect of Tongxinluo on Nephrin Expression via Inhibition of Notch1/Snail Pathway in Diabetic Rats

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Fangqiang Cui ◽  
Dawei Zou ◽  
Yanbin Gao ◽  
Na Zhang ◽  
Jinyang Wang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Molecular Mechanism ◽  
High Glucose ◽  
Diabetic Rats ◽  
In Vitro Studies ◽  
Podocyte Injury ◽  
Snail Expression ◽  
Renal Structure

Podocyte injury is an important mechanism of diabetic nephropathy (DN). Accumulating evidence suggests that nephrin expression is decreased in podocyte in DN. Moreover, it has been demonstrated that tongxinluo (TXL) can ameliorate renal structure disruption and dysfunction in DN. However, the effect of TXL on podocyte injury in DN and its molecular mechanism is unclear. In order to explore the effect of TXL on podocyte injury and its molecular mechanism in DN, our in vivo and in vitro studies were performed. Our results showed that TXL increased nephrin expression in diabetic rats and in high glucose cultured podocyte. Meanwhile, TXL decreased ICN1 (the intracellular domain of notch), HES1, and snail expression in podocyte in vivo and in vitro. More importantly, we found that TXL protected podocyte from injury in DN. The results demonstrated that TXL inhibited the activation of notch1/snail pathway and increased nephrin expression, which may be a mechanism of protecting effect on podocyte injury in DN.

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