scholarly journals MicroRNA-27a Promotes Oxidative-Induced RPE Cell Death through Targeting FOXO1

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Chengda Ren ◽  
Weinan Hu ◽  
Qingquan Wei ◽  
Wenting Cai ◽  
Huizi Jin ◽  
...  
Keyword(s):  
Cell Death ◽  
Rat Model ◽  
Cell Model ◽  
Retinal Function ◽  
Negative Regulator ◽  
Age Related Macular Degeneration ◽  
Luciferase Assay ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Foxo1 Gene

Age-related macular degeneration (AMD) is a multifactor disease, which is primarily characterized by retinal pigment epithelium (RPE) cell loss. Since the retina is the most metabolically active tissue, RPE cells are exposed to consistent oxidative environment. So, oxidation-induced RPE cell death has long been considered a contributor to the onset of AMD. Here, we applied a retinal degeneration (RD) rat model induced by blue light-emitting diode (LED) and a cell model constructed by H2O2 stimulus to mimic the prooxidant environment of the retina. We detected that the expression of miR-27a was upregulated and the expression of FOXO1 was downregulated in both models. So, we furtherly investigated the role of miR-27a-FOXO1 axis in RPE in protesting against oxidants. Lentivirus-mediated RNA was injected intravitreally into rats to modulate the miR-27a-FOXO1 axis. Retinal function and histopathological changes were evaluated by electroretinography (ERG) analysis and hematoxylin and eosin (H&E) staining, respectively. Massive photoreceptor and RPE cell death were examined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). The damage to the retina was aggravated in the FOXO1 gene-knockdown and miR-27a-overexpression groups after exposure to LED but was alleviated in the FOXO1 gene-overexpression or miR-27a-knockdown groups. Dual luciferase assay was used to detect the binding site of miR-27a and FOXO1. Upregulated miR-27a inhibited the expression of FOXO1 by directly binding to the FOXO1 mRNA 3 ′ UTR and decreased the autophagy activity of ARPE-19 cells, resulting in the accumulation of reactive oxygen species (ROS) and decrease of cell viability. The results suggest that miR-27a is a negative regulator of FOXO1. Also, our data emphasize the prominent role of miR-27a/FOXO1 axis in modulating ROS accumulation and cell death in RPE cell model under oxidative stress and influencing the retinal function in the LED-induced RD rat model.

scholarly journals 3,4-dehydro-L-proline Induces Programmed Cell Death in the Roots of Brachypodium distachyon

2021 ◽  
Vol 22 (14) ◽  
pp. 7548
Author(s):  
Artur Pinski ◽  
Alexander Betekhtin ◽  
Jolanta Kwasniewska ◽  
Lukasz Chajec ◽  
Elzbieta Wolny ◽  
...  
Keyword(s):  
Cell Death ◽  
Brachypodium Distachyon ◽  
Root Hairs ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Cell Wall Proteins ◽  
Root Epidermis ◽  
Root Hair Development ◽  
Transmission Electron ◽  
Hair Development

As cell wall proteins, the hydroxyproline-rich glycoproteins (HRGPs) take part in plant growth and various developmental processes. To fulfil their functions, HRGPs, extensins (EXTs) in particular, undergo the hydroxylation of proline by the prolyl-4-hydroxylases. The activity of these enzymes can be inhibited with 3,4-dehydro-L-proline (3,4-DHP), which enables its application to reveal the functions of the HRGPs. Thus, to study the involvement of HRGPs in the development of root hairs and roots, we treated seedlings of Brachypodium distachyon with 250 µM, 500 µM, and 750 µM of 3,4-DHP. The histological observations showed that the root epidermis cells and the cortex cells beneath them ruptured. The immunostaining experiments using the JIM20 antibody, which recognizes the EXT epitopes, demonstrated the higher abundance of this epitope in the control compared to the treated samples. The transmission electron microscopy analyses revealed morphological and ultrastructural features that are typical for the vacuolar-type of cell death. Using the TUNEL test (terminal deoxynucleotidyl transferase dUTP nick end labelling), we showed an increase in the number of nuclei with damaged DNA in the roots that had been treated with 3,4-DHP compared to the control. Finally, an analysis of two metacaspases’ gene activity revealed an increase in their expression in the treated roots. Altogether, our results show that inhibiting the prolyl-4-hydroxylases with 3,4-DHP results in a vacuolar-type of cell death in roots, thereby highlighting the important role of HRGPs in root hair development and root growth.

scholarly journals MiR-21-3p Promotes Hepatocellular Carcinoma Progression via SMAD7/YAP1 Regulation

2021 ◽  
Vol 11 ◽  
Author(s):  
Yinghui Hong ◽  
Mingliang Ye ◽  
Fan Wang ◽  
Jun Fang ◽  
Chun Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Signaling Pathway ◽  
Negative Regulator ◽  
Epigenetic Mechanism ◽  
Luciferase Assay ◽  
Rat Models ◽  
Cancer Pathogenesis ◽  
Tumor Stages

BackgroundHepatocellular carcinoma (HCC) remains a major global health burden due to its high prevalence and mortality. Emerging evidence reveals that microRNA (miRNA) plays a vital role in cancer pathogenesis and is widely involved in the regulation of signaling pathways via their targeting of downstream genes. MiR-21-3p, a liver-enriched miRNA, and SMAD7, the negative regulator of the TGF-β signaling pathway, likely exert a vital influence on HCC progression.AimsHere, we explore the role of the miR-21-3p-SMAD7/YAP1 axis on HCC pathogenesis.MethodsMiRNA microarray analysis was performed for miRNA screening. The dual-luciferase assay was adopted for target verification. Expression of miRNA and related genes were quantified via qRT-PCR, western blotting, and immunohistochemical staining. Flow cytometry and the transwell migration assay were used to detail cell apoptosis, invasion and metastases. Rat models were established to explore the role of the miR-21-3p-SMAD7/YAP1 axis in hepatocarcinogenesis. Bioinformatics analysis was conducted for exploring genes of clinical significance.ResultsMiR-21-3p levels were found to be significantly elevated in hepatocellular carcinoma and indicate poor overall survival. High miR-21-3p levels were associated with advanced tumor stages (P = 0.029), in particular T staging (P = 0.026). Low SMAD7/high YAP1 levels were confirmed in both HCC and rat models with advanced liver fibrosis and cirrhosis. Besides, SMAD7 was demonstrated to be the direct target of miR-21-3p. The effect of MiR-21-3p on tumor phenotypes and YAP1 upregulation could be partly reversed via the restoration of SMAD7 expression in HCC cell lines. Overexpression of YAP1 after miR-21-3p upregulation promoted expression of nuclear transcription effector connective tissue growth factor. Co-survival analysis indicated that lower miR-21-3p/higher SMAD7 (P = 0.0494) and lower miR-21-3p/lower YAP1 (P = 0.0379) group patients had better overall survival rates. Gene Set Variation Analysis revealed that gene sets related to miR-21-3p and SMAD7 were significantly associated with the TGF-β signaling pathway in HCC.ConclusionMiR-21-3p promotes migration and invasion of HCC cells and upregulation of YAP1 expression via direct inhibition of SMAD7, underscoring a major epigenetic mechanism in the pathogenesis of HCC.

scholarly journals Root-derived trans-zeatin cytokinin protects Arabidopsis plants against photoperiod stress

2020 ◽  
Author(s):  
Manuel Frank ◽  
Anne Cortleven ◽  
Ondrej Novak ◽  
Thomas Schmülling
Keyword(s):  
Cell Death ◽  
Response Regulator ◽  
Light Period ◽  
Negative Regulator ◽  
Marker Genes ◽  
Signaling Proteins ◽  
Negative Consequences ◽  
Regulatory Circuit ◽  
Cytokinin Synthesis

ABSTRACTRecently, a novel type of abiotic stress caused by a prolongation of the light period - coined photoperiod stress - has been described in Arabidopsis. During the night after the prolongation of the light period, stress and cell death marker genes are induced. The next day, strongly stressed plants display a reduced photosynthetic efficiency and leaf cells eventually enter programmed cell death. The phytohormone cytokinin (CK) acts as a negative regulator of this photoperiod stress syndrome. In this study, we show that Arabidopsis wild-type plants increase the CK concentration in response to photoperiod stress. Analysis of cytokinin synthesis and transport mutants revealed that root-derived trans-zeatin (tZ)-type CKs protect against photoperiod stress. The CK signaling proteins ARABIDOPSIS HISTIDINE PHOSPHOTRANSFER PROTEIN 2 (AHP2), AHP3 and AHP5 and transcription factors ARABIDOPSIS RESPONSE REGULATOR 2 (ARR2), ARR10 and ARR12 are required for the protective activity of CK. Analysis of higher order B-type arr mutants suggested that a complex regulatory circuit exists in which the loss of ARR10 or ARR12 can rescue the arr2 phenotype. Together the results revealed the role of root-derived CK acting in the shoot through the two-component signaling system to protect from the negative consequences of strong photoperiod stress.

scholarly journals Stim1 Deletion Synthetically Rescues Ezh2-Null Effector T Cells and Alloimmunity

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4533-4533
Author(s):  
Ying Wang ◽  
Shan He ◽  
Yongnian Liu ◽  
Robert Hooper ◽  
Hongshuang Yu ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Effector T Cells ◽  
Conditional Knockout ◽  
Negative Regulator ◽  
Sequencing Analysis ◽  
Major Barrier ◽  
Donor T Cells

Abstract Graft-versus-host disease (GVHD) remains a major barrier for the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have identified the central role of the histone methyltransferase Ezh2 in regulating allogeneic T-cell expansion, differentiation and function. Conditional loss of Ezh2 in donor T cells inhibits GVHD in mice due to the inability of alloreactive T cells to persist. However, the molecular mechanism by which Ezh2 deficiency causes alloreactive T cell death remains unknown. Here we demonstrate that genetic deletion of Stromal Interaction Molecule (Stim) 1, a dynamic endoplasmic reticulum Ca2+ sensor and regulator of Ca2+ signaling, rescues antigen-activated Ezh2-null (Ezh2-/-) T cells, leading to restored persistence of alloreactive effector T cells in mice and severe GVHD. Using RNA-sequencing analysis, we found Ezh2-deficiency led to the upregulation of multiple genes (e.g., Ifng, Prf1, Ccl5, Ccl4, Upp1 and Spp1) known to be regulated by Ca2+ signals through calcineurin (CN), the primary target of the immunosuppressant cyclosporine A (CsA). This reverse correlation between Ezh2 inhibition and CsA-treatment for gene expression suggests that Ezh2 may antagonize Ca2+ signaling in activated T cells. Calcium signaling assays revealed higher cytosolic Ca2+ uptake and more frequent Ca2+ oscillations in Ezh2-/- T cells. Moreover, Ezh2-/- T cells exhibited significantly increased polarization of Stim1 and Orai1 in the cellular membrane. These data reveal an unexpected role of Ezh2 as a negative regulator of Ca2+ entry, thereby serving as a 'brake' for Ca2+ signaling. Using the C57BL/6 (B6) into Balb/c mouse GVHD model, we found significantly fewer Ezh2-/- or Stim1-/- IFN-g-secreting effector T cells compared to the WT counterparts on day 8 or 14 post-transplantation. In contrast, deleting Stim1 from Ezh2-/- donor T cells rescued the cells in the spleen and liver, producing even more donor T cells and IFN-g-secreting effector T cells compared to WT T cells and inducing severe GVHD. We further examined the cell autonomous effect of Stim1 deletion on the rescue of Ezh2-/- T cells by mixing WT T cells (B6/SJL, CD45.1) with Ezh2- and/or Stim1- conditional knockout T cells (i.e., Ezh2-/-, Stim1-/- or Ezh2-/- x Stim1-/- B6 T cells (CD45.2)) at a ratio of 1:1 before transferring into the Balb/c mice. While loss of either Ezh2 or Stim1 led to lower frequency of IFN-g+IL-2+ effector T cells, combined deletion of both genes restored the frequency and number of IFN-g+IL-2+ effector T cells to that of WT T cells. Thus, Stim1-mediated Ca2+ signals are crucial for mediating cell death in alloantigen-driven Ezh2-/- effector T cells. To further determine whether the inhibition of CN-NFAT contributes to the rescue, we treated T cell receptor (TCR)-activated Ezh2-/- T cells with CsA or the calcium release-activated channel specific inhibitor BTP2, respectively, in vitro. While BTP2 dramatically improved the survival of IFN-g-producing effector T cells, CsA did not, suggesting the involvement of CN-NFAT-independent pathways. Ca2+ overload is known to impair mitochondrial function and cause massive cell death. As compared to TCR-activated WT T cells, activated Ezh2-/- T cells displayed significantly less ATP, lower mitochondrial membrane potential, enlarged mitochondrial mass, and decreased capacity to upregulate oxidative phosphorylation. Stim1 deletion largely reversed the metabolic defect in Ezh2-/- T cells, indicating the critical role of mitochondrial metabolism in rescuing these T cells. Considered together, our findings identify the remarkable coordination between Ezh2- and Stim1-regulated effector T cell persistence. As such, these investigations may lead to new approaches to inhibit GVHD, with broad implications to defining fundamental mechanisms of T cell differentiation for control of adaptive immunity, such as tumor immunity and autoimmunity. Disclosures Reshef: Incyte: Consultancy; Takeda Pharmaceuticals: Consultancy; Pfizer: Consultancy; Kite Pharma: Consultancy; Atara Biotherapeutics: Consultancy; Bristol-Myers Squibb: Consultancy.

Activation of ATF3/AP-1 signaling pathway is required for P2X3-induced endometriosis pain

2020 ◽  
Vol 35 (5) ◽  
pp. 1130-1144 ◽  
Author(s):  
Shaojie Ding ◽  
Qin Yu ◽  
Jianzhang Wang ◽  
Libo Zhu ◽  
Tiantian Li ◽  
...  
Keyword(s):  
Delivery System ◽  
Rat Model ◽  
Large Scale ◽  
Nerve Fibers ◽  
Luciferase Assay ◽  
Chitosan Oligosaccharide ◽  
P2x3 Receptor ◽  
Rat Models ◽  
Expression Levels

Abstract STUDY QUESTION Does P2X ligand-gated ion channel 3 (P2X3) play a role in endometriosis pain? SUMMARY ANSWER Upregulation of P2X3 in dorsal root ganglia (DRG) tissues via the activating transcription factor 3 (ATF3)/activator protein (AP)-1 pathway contributed to endometriosis-associated hyperalgesia, which could be attenuated by the chitosan oligosaccharide stearic acid (CSOSA)/liposomes (LPs)/SP600125 delivery system. WHAT IS KNOWN ALREADY Infiltrating nerve fibers and elevated nociceptors in endometriotic lesions are associated with endometriosis pain. P2X3 has been demonstrated to play an important role in neuropathic pain. STUDY DESIGN, SIZE, DURATION A rat model of endometriosis was used to investigate the signaling pathways involved in P2X3-induced pain. PARTICIPANTS/MATERIALS, SETTING, METHODS Degrees of hyperalgesia, endogenous adenosine 5′-triphosphate (ATP) contents and P2X3 expression levels in endometriotic lesions and DRG tissues were detected in a rat model of endometriosis. The expression levels of ATF3 and P2X3 were measured using qRT-PCR, western blot analysis and immunofluorescence analysis after adenosine 5′-diphosphate (ADP) exposure in DRG cells. Plasmids encoding ATF3 and its siRNA were used to investigate the role of ATF3 on ADP-induced P2X3 upregulation. The activity of ATF binding to the P2X3 promoter was evaluated by using chromatin immunoprecipitation (CHIP) and luciferase assays. SP600125, an inhibitor of c-JUN N-terminal kinase, was wrapped in CSOSA/LPs delivery system and its inhibitory effects on ADP-induced upregulation of P2X3 in DRG cells and endometriosis-induced hyperalgesia in rats were tested. MAIN RESULTS AND THE ROLE OF CHANCE The concentrations of endogenous ATP and expression levels of P2X3 were significantly increased in both endometriotic lesions and DRG tissues in endometriosis rat models and were found to be positively correlated with the severity of hyperalgesia. In DRG cells, P2X3 expression levels were elevated by ADP stimulation, but dramatically inhibited by blocking ATF3 with its siRNA and SP600125. CHIP and luciferase assay showed that ADP increased the binding of ATF3 to the P2X3 promoter, resulting in an increase in P2X3 expression levels. In the CSOSA/LPs/SP600125 delivery system, the drug could be effectively concentrated in endometriotic lesions, and it could alleviate endometriosis-induced hyperalgesia, reduce the size of endometriotic lesions and attenuate upregulated P2X3 expression levels in endometriosis rat models. LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION Changes in the sensitivity and function of P2X3 caused by endometriosis need to be further investigated. WIDER IMPLICATIONS OF THE FINDINGS This study indicates that ATP and the P2X3 receptor are involved in endometriosis pain, thus providing a novel therapeutic approach for the treatment of endometriosis pain by targeting the P2X3 receptor. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by National Key R&D Program of China (Grant No. 2017YFC1001202) and National Natural Science Foundation of China (Grant Nos. 81974225, 81671429 and 81471433). There are no competing interests.

Hydrogen sulfide and its possible roles in myocardial ischemia in experimental rats

2007 ◽  
Vol 102 (1) ◽  
pp. 261-268 ◽  
Author(s):  
Yi Zhun Zhu ◽  
Zhong Jing Wang ◽  
Peiying Ho ◽  
Yoke Yun Loke ◽  
Yi Chun Zhu ◽  
...  
Keyword(s):  
Cell Death ◽  
Hydrogen Sulfide ◽  
Rat Model ◽  
Protein Localization ◽  
Sodium Hydrosulfide ◽  
Infarct Area ◽  
Novel Approach ◽  
First Time

The role of hydrogen sulfide (H2S) in myocardial infarction (MI) has not been previously studied. We therefore investigated the effect of H2S in a rat model of MI in vivo. Animals were randomly divided into three groups ( n = 80) and received either vehicle, 14 μmol/kg of sodium hydrosulfide (NaHS), or 50 mg/kg propargylglycine (PAG) everyday for 1 wk before surgery, and the treatment was continued for a further 2 days after MI when the animals were killed. The mortality was 35% in vehicle-treated, 40% in PAG-treated, and 27.5% in NaHS-treated ( P < 0.05 vs. vehicle) groups. Infarct size was 52.9 ± 3.5% in vehicle-treated, 62.9 ± 7.6% in PAG-treated, and 43.4 ± 2.8% in NaHS-treated ( P < 0.05 vs. vehicle) groups. Plasma H2S concentration was significantly increased after MI (59.2 ± 7.16 μM) compared with the baseline concentration (i.e., 38.2 ± 2.07 μM before MI; P < 0.05). Elevated plasma H2S after MI was abolished by treatment of animals with PAG (39.2 ± 5.02 μM). We further showed for the first time cystathionine-gamma-lyase protein localization in the myocardium of the infarct area by using immunohistochemical staining. In the hypoxic vascular smooth muscle cells, we found that cell death was increased under the stimuli of hypoxia but that the increased cell death was attenuated by the pretreatment of NaHS (71 ± 1.2% cell viability in hypoxic vehicle vs. 95 ± 2.3% in nonhypoxic control; P < 0.05). In conclusion, endogenous H2S was cardioprotective in the rat model of MI. PAG reduced endogenous H2S production after MI by inhibiting cystathionine-gamma-lyase. The results suggest that H2S might provide a novel approach to the treatment of MI.

scholarly journals Hyperuricemia Predisposes to the Onset of Diabetes via Promoting Pancreatic β-Cell Death in Uricase Deficiency Male Mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Jie Lu ◽  
Yuwei He ◽  
Lingling Cui ◽  
Xiaoming Xing ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Kidney Injury ◽  
Serum Urate ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Diabetes Incidence ◽  
Β Cell ◽  
External Stimulation ◽  
Urate Lowering Treatment

Clinical studies have shown a link between hyperuricemia (HU) and diabetes, while the exact effect of soluble serum urate on glucose metabolism remains elusive. This study aims to characterize the glucose metabolic phenotypes and investigate the underlying molecular mechanisms using a novel spontaneous HU mouse model which is in absence of <i>Uricase</i> (<i>Uox</i>) gene. In an attempt to study the role of HU in glycometabolism, we implemented external stimulation on <i>Uox</i>-knockout (KO) and wild-type (WT) males with high-fat diet (HFD) and (/or) multiple-low-dose streptozotocin (MLD-STZ) to provoke the potential role of urate. Notably, while <i>Uox</i><i>-</i>KO mice developed glucose intolerance in basal condition, none had spontaneously developed into diabetes even with aging. HFD-fed <i>Uox</i><i>-</i>KO mice manifested similar insulin sensitivity compared with WT controls. HU augmented the existing glycometabolism abnormality induced by MLD-STZ, and eventually lead to diabetes evidenced by the increased random glucose. Reduced β cell masses and increased the terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) positive <a>β cell</a>s suggested HU-mediated diabetes was cell death dependent. However, urate-lowering treatment (ULT) cannot ameliorate the diabetes incidence nor reverse β-cell apoptosis with significance. While, ULT displayed a significant therapeutic effect of hyperuricemic-crystal associated kidney injury and tubulointerstitial damage in diabetes. Moreover, we present transcriptomic analysis of isolated islets, using <i>Uox</i>-KO <i>versus</i> WT mice and streptozotocin-induced diabetic WT (STZ-WT) <i>versus</i><i> </i>diabetic <i>Uox</i>-KO (STZ-KO) mice. Shared differentially expressed genes of HU primacy revealed Stk17β is a possible target gene in HU related β-cell death. Together, this study suggests that HU accelerates but not causes diabetes by inhibiting islet β-cell survival.

scholarly journals Autophagy Dynamics and Modulation in a Rat Model of Renal Ischemia-Reperfusion Injury

2020 ◽  
Vol 21 (19) ◽  
pp. 7185
Author(s):  
Jean-Paul Decuypere ◽  
Shawn Hutchinson ◽  
Diethard Monbaliu ◽  
Wim Martinet ◽  
Jacques Pirenne ◽  
...  
Keyword(s):  
Cell Death ◽  
Rat Model ◽  
Renal Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mammalian Target Of Rapamycin ◽  
Treatment Strategies ◽  
Kidney Injury ◽  
Renal Ischemia

Renal ischemia-reperfusion (IR) injury leading to cell death is a major cause of acute kidney injury, contributing to morbidity and mortality. Autophagy counteracts cell death by removing damaged macromolecules and organelles, making it an interesting anchor point for treatment strategies. However, autophagy is also suggested to enhance cell death when the ischemic burden is too strong. To investigate whether the role of autophagy depends on the severity of ischemic stress, we analyzed the dynamics of autophagy and apoptosis in an IR rat model with mild (45 min) or severe (60 min) renal ischemia. Following mild IR, renal injury was associated with reduced autophagy, enhanced mammalian target of rapamycin (mTOR) activity, and apoptosis. Severe IR, on the other hand, was associated with a higher autophagic activity, independent of mTOR, and without affecting apoptosis. Autophagy stimulation by trehalose injected 24 and 48 h prior to onset of severe ischemia did not reduce renal injury markers nor function, but reduced apoptosis and restored tubular dilation 7 days post reperfusion. This suggests that trehalose-dependent autophagy stimulation enhances tissue repair following an IR injury. Our data show that autophagy dynamics are strongly dependent on the severity of IR and that trehalose shows the potential to trigger autophagy-dependent repair processes following renal IR injury.

scholarly journals Hyperuricemia Predisposes to the Onset of Diabetes via Promoting Pancreatic β-Cell Death in Uricase Deficiency Male Mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Jie Lu ◽  
Yuwei He ◽  
Lingling Cui ◽  
Xiaoming Xing ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Kidney Injury ◽  
Serum Urate ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Diabetes Incidence ◽  
Β Cell ◽  
External Stimulation ◽  
Urate Lowering Treatment

Clinical studies have shown a link between hyperuricemia (HU) and diabetes, while the exact effect of soluble serum urate on glucose metabolism remains elusive. This study aims to characterize the glucose metabolic phenotypes and investigate the underlying molecular mechanisms using a novel spontaneous HU mouse model which is in absence of <i>Uricase</i> (<i>Uox</i>) gene. In an attempt to study the role of HU in glycometabolism, we implemented external stimulation on <i>Uox</i>-knockout (KO) and wild-type (WT) males with high-fat diet (HFD) and (/or) multiple-low-dose streptozotocin (MLD-STZ) to provoke the potential role of urate. Notably, while <i>Uox</i><i>-</i>KO mice developed glucose intolerance in basal condition, none had spontaneously developed into diabetes even with aging. HFD-fed <i>Uox</i><i>-</i>KO mice manifested similar insulin sensitivity compared with WT controls. HU augmented the existing glycometabolism abnormality induced by MLD-STZ, and eventually lead to diabetes evidenced by the increased random glucose. Reduced β cell masses and increased the terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) positive <a>β cell</a>s suggested HU-mediated diabetes was cell death dependent. However, urate-lowering treatment (ULT) cannot ameliorate the diabetes incidence nor reverse β-cell apoptosis with significance. While, ULT displayed a significant therapeutic effect of hyperuricemic-crystal associated kidney injury and tubulointerstitial damage in diabetes. Moreover, we present transcriptomic analysis of isolated islets, using <i>Uox</i>-KO <i>versus</i> WT mice and streptozotocin-induced diabetic WT (STZ-WT) <i>versus</i><i> </i>diabetic <i>Uox</i>-KO (STZ-KO) mice. Shared differentially expressed genes of HU primacy revealed Stk17β is a possible target gene in HU related β-cell death. Together, this study suggests that HU accelerates but not causes diabetes by inhibiting islet β-cell survival.

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