المؤلفون: Fawaz, Sarah, Martin Alonso, Aldara, Qiu, Yan, Ramnath, Raina, Stowell-Connolly, Holly, Gamez, Monica, May, Carl, Down, Colin, Coward, Richard J, Butler, Matthew J, Welsh, Gavin I, Satchell, Simon C, Foster, Rebecca R

المصدر: Fawaz , S , Martin Alonso , A , Qiu , Y , Ramnath , R , Stowell-Connolly , H , Gamez , M , May , C , Down , C , Coward , R J , Butler , M J , Welsh , G I , Satchell , S C & Foster , R R 2024 , ' Adiponectin Reduces Glomerular Endothelial Glycocalyx Disruption and Restores Glomerular Barrier Function in a Mouse Model of Type 2 Diabetes ' , Diabetes , vol. 73 , no. 6 , pp. 964-976 . https://doi.org/10.2337/db23-0455Test

مصطلحات موضوعية: Animals, Glycocalyx/metabolism, Adiponectin/metabolism, Mice, Diabetes Mellitus, Type 2/metabolism, Kidney Glomerulus/metabolism, Humans, Diabetic Nephropathies/metabolism, Endothelial Cells/metabolism, Male, Glomerular Filtration Barrier/metabolism, Tumor Necrosis Factor-alpha/metabolism, Syndecan-4/metabolism, Disease Models, Animal, Inbred C57BL

الوصف: Adiponectin has vascular anti-inflammatory and protective effects. Although adiponectin protects against the development of albuminuria, historically, the focus has been on podocyte protection within the glomerular filtration barrier (GFB). The first barrier to albumin in the GFB is the endothelial glycocalyx (eGlx), a surface gel-like barrier covering glomerular endothelial cells (GEnCs). In diabetes, eGlx dysfunction occurs before podocyte damage; hence, we hypothesized that adiponectin could protect from eGlx damage to prevent early vascular damage in diabetic kidney disease (DKD). Globular adiponectin (gAd) activated AMPK signaling in human GEnCs through AdipoR1. It significantly reduced eGlx shedding and the tumor necrosis factor-α (TNF-α)-mediated increase in syndecan-4 (SDC4) and MMP2 mRNA expression in GEnCs in vitro. It protected against increased TNF-α mRNA expression in glomeruli isolated from db/db mice and against expression of genes associated with glycocalyx shedding (namely, SDC4, MMP2, and MMP9). In addition, gAd protected against increased glomerular albumin permeability (Ps'alb) in glomeruli isolated from db/db mice when administered intraperitoneally and when applied directly to glomeruli (ex vivo). Ps'alb was inversely correlated with eGlx depth in vivo. In summary, adiponectin restored eGlx depth, which was correlated with improved glomerular barrier function, in diabetes.

العلاقة: https://research-information.bris.ac.uk/en/publications/d783d5a6-17c2-49b2-897a-a8f7bad3c6e6Test

الإتاحة: https://doi.org/10.2337/db23-0455Test
https://hdl.handle.net/1983/d783d5a6-17c2-49b2-897a-a8f7bad3c6e6Test
https://research-information.bris.ac.uk/en/publications/d783d5a6-17c2-49b2-897a-a8f7bad3c6e6Test

المؤلفون: Lay, Abigail C., Hale, Lorna J., Stowell-Connolly, Holly, Pope, Robert J. P., Nair, Viji, Ju, Wenjun, Marquez, Eva, Rollason, Ruth, Hurcombe, Jenny A., Hayes, Bryony, Roberts, Timothy, Gillam, Lawrence, Allington, Jonathan, Nelson, Robert G., Kretzler, Matthias, Holly, Jeff M. P., Perks, Claire M., McArdle, Craig A., Welsh, Gavin I., Coward, Richard J. M.

المصدر: Lay , A C , Hale , L J , Stowell-Connolly , H , Pope , R J P , Nair , V , Ju , W , Marquez , E , Rollason , R , Hurcombe , J A , Hayes , B , Roberts , T , Gillam , L , Allington , J , Nelson , R G , Kretzler , M , Holly , J M P , Perks , C M , McArdle , C A , Welsh , G I & Coward , R J M 2021 , ' IGFBP-1 expression is reduced ....

مصطلحات موضوعية: Biopsy, Cells, Cultured, Cohort Studies, Diabetes Mellitus, Type 2/genetics, Diabetic Nephropathies/genetics, Endothelial Cells/metabolism, Focal Adhesion Protein-Tyrosine Kinases/metabolism, Humans, Insulin-Like Growth Factor Binding Protein 1/genetics, Integrin beta1/metabolism, Kidney Glomerulus/metabolism, Kidney/metabolism, Podocytes/metabolism, Signal Transduction/genetics

الوصف: AIMS/HYPOTHESIS: Podocyte loss or injury is one of the earliest features observed in the pathogenesis of diabetic kidney disease (DKD), which is the leading cause of end-stage renal failure worldwide. Dysfunction in the IGF axis, including in IGF binding proteins (IGFBPs), is associated with DKD, particularly in the early stages of disease progression. The aim of this study was to investigate the potential roles of IGFBPs in the development of type 2 DKD, focusing on podocytes. METHODS: IGFBP expression was analysed in the Pima DKD cohort, alongside data from the Nephroseq database, and in ex vivo human glomeruli. Conditionally immortalised human podocytes and glomerular endothelial cells were studied in vitro, where IGFBP-1 expression was analysed using quantitative PCR and ELISAs. Cell responses to IGFBPs were investigated using migration, cell survival and adhesion assays; electrical cell-substrate impedance sensing; western blotting; and high-content automated imaging. RESULTS: Data from the Pima DKD cohort and from the Nephroseq database demonstrated a significant reduction in glomerular IGFBP-1 in the early stages of human type 2 DKD. In the glomerulus, IGFBP-1 was predominantly expressed in podocytes and controlled by phosphoinositide 3-kinase (PI3K)-forkhead box O1 (FoxO1) activity. In vitro, IGFBP-1 signalled to podocytes via β1-integrins, resulting in increased phosphorylation of focal-adhesion kinase (FAK), increasing podocyte motility, adhesion, electrical resistance across the adhesive cell layer and cell viability. CONCLUSIONS/INTERPRETATION: This work identifies a novel role for IGFBP-1 in the regulation of podocyte function and that the glomerular expression of IGFBP-1 is reduced in the early stages of type 2 DKD, via reduced FoxO1 activity. Thus, we hypothesise that strategies to maintain glomerular IGFBP-1 levels may be beneficial in maintaining podocyte function early in DKD.

العلاقة: https://research.manchester.ac.uk/en/publications/3c0ee8a7-3759-48f8-b456-543c038b2c03Test

الإتاحة: https://doi.org/10.1007/s00125-021-05427-1Test
https://research.manchester.ac.uk/en/publications/3c0ee8a7-3759-48f8-b456-543c038b2c03Test

المؤلفون: Nunes, S, Alves, A, Preguiça, I, Barbosa, A, Vieira, P, Mendes, F, Martins, D, Viana, SD, Reis, F

المساهمون: Instituto de Investigação e Inovação em Saúde

مصطلحات موضوعية: Animals, Biomarkers, Body Weight, Collagen Type IV / metabolism, Diabetic Nephropathies / etiology, Diabetic Nephropathies / metabolism, Diabetic Nephropathies / pathology, Diet, Diabetic / adverse effects, Disease Models, Animal, Energy Intake, Immunohistochemistry, Kidney Function Tests, Kidney Glomerulus / metabolism, Kidney Glomerulus / pathology, Lipid Metabolism, Male, Prediabetic State / complications, Prediabetic State / etiology, Prediabetic State / metabolismo, Rats

الوصف: Diabetic nephropathy (DN) is a major microvascular complication of diabetes. Obesity and hyperlipidemia, fueled by unhealthy food habits, are risk factors to glomerular filtration rate (GFR) decline and DN progression. Several studies recommend that diabetic patients should be screened early (in prediabetes) for kidney disease, in order to prevent advanced stages, for whom the current interventions are clearly inefficient. This ambition greatly depends on the existence of accurate early biomarkers and novel molecular targets, which only may arise with a more thorough knowledge of disease pathophysiology. We used a rat model of prediabetes induced by 23 weeks of high-sugar/high-fat (HSuHF) diet to characterize the phenotype of early renal dysfunction and injury. When compared with the control animals, HSuHF-treated rats displayed a metabolic phenotype compatible with obese prediabetes, displaying impaired glucose tolerance and insulin sensitivity, along with hypertriglyceridemia, and lipid peroxidation. Despite unchanged creatinine levels, the prediabetic animals presented glomerular crescent-like lesions, accompanied by increased kidney Oil-Red-O staining, triglycerides content and mRNA expression of IL-6 and iNOS. This model of HSuHF-induced prediabetes can be a useful tool to study early features of DN, namely crescent-like lesions, an early signature that deserves in-depth elucidation. ; This work was supported by the European Regional Development Fund (FEDER), through Programa Operacional Factores de Competitividade COMPETE2020 (CENTRO-01-0145-FEDER-000012-HealthyAging2020) and by National funds via Portuguese Science and Technology Foundation (FCT): Strategic Projects UID/NEU/04539/2013, UID/NEU/04539/2019, UIDB/04539/2020 and UIDP/04539/2020 (CIBB), SFRH/BD/109017/2015 (PhD Fellowship) and PTDC/SAU-NUT/31712/2017, as well as by COMPETE-FEDER funds (POCI-01-0145-FEDER-007440 and POCI-01-0145-FEDER-031712).

وصف الملف: application/pdf

العلاقة: info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FNEU%2F04539%2F2013/PT; info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FNEU%2F04539%2F2019/PT; info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04539%2F2020/PT; Nutrients, vol.12(4):881; https://www.mdpi.com/2072-6643/12/4/881Test; https://hdl.handle.net/10216/142504Test

الإتاحة: https://doi.org/10.3390/nu12040881Test
https://hdl.handle.net/10216/142504Test

المساهمون: College of Medicine, Dept. of Pediatrics, SUNG�멐UN CHOI, NARA JEON, HOON YOUNG CHOI, JAE IL SHIN, HYEON JOO JEONG, BEOM JIN LIM, Shin, Jae Il, Lim, Beom Jin, Jeong, Hyeon Joo, Choi, Hoon Young

مصطلحات موضوعية: Amino Acid Oxidoreductases/analysis, Amino Acid Oxidoreductases/genetics, Animals, Cell Line, Disease Progression, Fibrosis, Gene Expression Regulation, Humans, Kidney/metabolism, Kidney/pathology, Kidney Glomerulus/metabolism, Kidney Glomerulus/pathology, Kidney Tubules/metabolism, Kidney Tubules/pathology, Male, Mice, Podocytes/metabolism, Podocytes/pathology, Renal Insufficiency, Chronic/genetics, Chronic/pathology

الوصف: Tubulointerstitial fibrosis is a common end point of chronic kidney diseases, and preventing its progression is key to avoiding renal failure. Transforming growth factor�뫮� (TGF�뫮�) and associated molecules promote tubulointerstitial fibrosis; however, effective therapies targeting these molecules have yet to be developed. Lysyl oxidase�멿ike 2 (LOXL2), which is involved in invasive growth and metastasis of malignant neoplasms, has recently been reported to serve a key role in hepatic and pulmonary fibrosis. However, little is currently known regarding LOXL2 expression in the kidney and its involvement in tubulointerstitial fibrosis. The present study evaluated LOXL2 expression in human and mouse kidney tissues, as well as in cultured renal cells. LOXL2 protein expression was detected in glomerular capillary loops and tubular epithelial cells in human and mouse kidneys. Glomerular LOXL2 was localized to the cytoplasm of podocytes, as determined by double immunofluorescence microscopy using a podocyte marker (synaptopodin). This result was supported by western blot analysis, which demonstrated that LOXL2 protein expression is present in cultured human podocytes and HK��2 human proximal tubular cells. In addition, the mRNA and protein expression levels of LOXL2 were higher in a mouse model of tubulointerstitial fibrosis compared with in control mice. In addition, immunohistochemistry results demonstrated that LOXL2 is present in the fibrous interstitium and infiltrating mononuclear cells in a mouse model of tubulointerstitial fibrosis. The present study demonstrated that LOXL2 is expressed in compartments of renal tissue, where it appears to contribute to the progression of tubulointerstitial fibrosis. ; open

وصف الملف: application/pdf

العلاقة: MOLECULAR MEDICINE REPORTS; J02261; OAK-2017-03520; https://ir.ymlib.yonsei.ac.kr/handle/22282913/160422Test; T201702351; MOLECULAR MEDICINE REPORTS, Vol.16(3) : 2477-2482, 2017

الإتاحة: https://doi.org/10.3892/mmr.2017.6918Test
https://ir.ymlib.yonsei.ac.kr/handle/22282913/160422Test

المساهمون: College of Medicine, Dept. of Internal Medicine, Jisun Paeng, Jimin Park, Jae Eun Um, Bo Young Nam, Hye-Young Kang, Seonghun Kim, Hyung Jung Oh, Jung Tak Park, Seung Hyeok Han, Dong-Ryeol Ryu, Tae-Hyun Yoo, Shin-Wook Kang, Kang, Shin Wook, Nam, Bo Young, Park, Jung Tak, Yoo, Tae Hyun, Han, Seung Hyeok

مصطلحات موضوعية: Albumins/metabolism, Angiotensin II/genetics, Angiotensin II/metabolism, Angiotensinogen/genetics, Angiotensinogen/metabolism, Animals, Cell Membrane Permeability/drug effects, Cells, Cultured, Diabetes Mellitus, Experimental/metabolism, Experimental/pathology, Endothelial Cells/drug effects, Endothelial Cells/metabolism, Glucose/pharmacology, Humans, Kidney Glomerulus/drug effects, Kidney Glomerulus/metabolism, Kidney Glomerulus/pathology, Male, Rats, Sprague-Dawley, Receptor, Angiotensin, Type 1/genetics, Type 1/metabolism, Renin-Angiotensin System/drug effects, Sweetening Agents/pharmacology, albuminuria, diabetic nephropathy

الوصف: BACKGROUND: Although the diabetic milieu per se , hemodynamic changes, oxidative stress and local growth factors such as angiotensin II (AII) are considered to be mediators in the pathogenesis of diabetic nephropathy, the underlying pathways mediating the changes in glomerular endothelial cells (GECs) are not well understood. Therefore, we investigated changes in the renin-angiotensin system (RAS) components in high glucose (HG)-stimulated GECs and the role of the local RAS in morphological and functional changes in GECs under diabetic conditions. METHODS: We stimulated GECs with 5.6 mM glucose or 30 mM glucose with or without an angiotensin II type I receptor blocker (ARB) in vitro and also performed experiments with Sprague-Dawley rats injected with diluent ( n = 16) or streptozotocin [ n = 16, diabetes (DM)]. Eight rats from each group were treated with ARB for 3 months in vivo . Real-time polymerase chain reaction, western blot analysis, enzyme-linked immunosorbent assay and immunofluorescent staining using cultured GECs were performed. The permeability of GECs to macromolecules was assessed by measuring the passage of fluorescein isothiocyanate-labeled bovine serum albumin. Morphological changes were also evaluated by scanning and transmission electron microscopy. RESULTS: There were significant increases in angiotensinogen expression in HG-stimulated GECs along with significant increases in AI and AII levels. Moreover, the expression of heparan sulfate glycosaminoglycans (HS-GAG) assessed by immunofluorescent staining was significantly lower and the permeability to albumin was significantly higher in GECs exposed to HG medium, and ARB treatment significantly abrogated these changes. Upon electron microscopy examination, the mean size of the GEC fenestrae was significantly greater in HG-stimulated GECs and DM rats, and these increases were significantly ameliorated by ARB. CONCLUSIONS: The local RAS within GECs was activated under HG conditions, and this activation may be associated with both an alteration ...

العلاقة: NEPHROLOGY DIALYSIS TRANSPLANTATION; J02316; OAK-2017-01800; https://ir.ymlib.yonsei.ac.kr/handle/22282913/154626Test; T201701205; NEPHROLOGY DIALYSIS TRANSPLANTATION, Vol.32(1) : 61-72, 2017

الإتاحة: https://doi.org/10.1093/ndt/gfw089Test
https://ir.ymlib.yonsei.ac.kr/handle/22282913/154626Test

المساهمون: College of Medicine, Dept. of Internal Medicine, Dong Ho Shin, Beom Jin Lim, In Mi Han, Seung Gyu Han, Young Eun Kwon, Kyoung Sook Park, Mi Jung Lee, Hyung Jung Oh, Jung Tak Park, Seung Hyeok Han, Shin-Wook Kang, Tae-Hyun Yoo, Kang, Shin Wook, Han, Seung Hyeok, Kwon, Young Eun, Park, Jung Tak, Yoo, Tae Hyun, Lim, Beom Jin

مصطلحات موضوعية: Adult, Arterial Pressure/physiology, Disease Progression, Female, Glomerular Filtration Rate/physiology, Glomerulonephritis, IGA/metabolism, IGA/pathology, IGA/physiopathology, Humans, Immunoglobulin G/metabolism, Kidney/metabolism, Kidney/pathology, Kidney/physiopathology, Kidney Failure, Chronic/metabolism, Chronic/pathology, Chronic/physiopathology, Kidney Glomerulus/metabolism, Kidney Glomerulus/pathology, Kidney Glomerulus/physiopathology, Male, Prognosis

الوصف: Glomerular IgG deposition is frequently observed in patients with IgA nephropathy. However, the association between glomerular IgG deposition and progression of IgA nephropathy is uncertain. Six hundred and twenty-seven patients with biopsy-proven IgA nephropathy were recruited. Histological variables of the Oxford classification (Oxford-MEST) and the presence of glomerular IgG deposits were assessed. Renal progression defined as end-stage renal disease or 50% reduction in estimated glomerular filtration rate was analyzed using Kaplan-Meier methods and Cox regression analysis. Of the study population, 200 patients (31.9%) had glomerular IgG deposition on immunofluorescence staining. During a mean follow-up of 56.8짹37.5 months, the rate of renal progression was significantly higher in the IgA nephropathy patients with glomerular IgG deposition compared with the IgA nephropathy patients without glomerular IgG deposition (39.8 vs 12.3 per 1000 patient-years; P<0.001). Of patients with IgG deposition, 178 (28.3%), 20 (3.2%), and 2 (0.3%) patients had mild, moderate, and marked glomerular IgG deposits, receptively. Kaplan-Meier analysis revealed that cumulative renal survival was significantly lower in IgA nephropathy patients with the higher intensity of glomerular IgG deposits (P<0.001). In addition, Cox regression analysis revealed that moderate and marked glomerular IgG deposits significantly predicted renal outcome independent of Oxford-MEST and clinical variables (HR, 2.97; 95% CI, 1.01-8.77; P=0.04). This study showed that that glomerular IgG deposition was independently associated with poor renal outcome in patient with IgA nephropathy. ; restriction

العلاقة: MODERN PATHOLOGY; J02238; OAK-2016-03897; https://ir.ymlib.yonsei.ac.kr/handle/22282913/151628Test; http://www.nature.com/modpathol/journal/v29/n7/full/modpathol201677a.htmlTest; T201602374; MODERN PATHOLOGY, Vol.29(7) : 743-752, 2016

الإتاحة: https://doi.org/10.1038/modpathol.2016.77Test
https://ir.ymlib.yonsei.ac.kr/handle/22282913/151628Test
http://www.nature.com/modpathol/journal/v29/n7/full/modpathol201677a.htmlTest

المؤلفون: Jones, Frances E, Bailey, Matthew A, Murray, Lydia S, Lu, Yinhui, McNeilly, Sarah, Schlötzer-Schrehardt, Ursula, Lennon, Rachel, Sado, Yoshikazu, Brownstein, David G, Mullins, John J, Kadler, Karl E, Van Agtmael, Tom

المصدر: Jones , F E , Bailey , M A , Murray , L S , Lu , Y , McNeilly , S , Schlötzer-Schrehardt , U , Lennon , R , Sado , Y , Brownstein , D G , Mullins , J J , Kadler , K E & Van Agtmael , T 2016 , ' ER stress and basement membrane defects combine to cause glomerular and tubular renal disease resulting from Col4a1 mutations in mice. ' , DMM Disease Models and Mechanisms , vol. 9 , no. 2 , pp. 165-76 . https://doi.org/10.1242/dmm.021741Test , https://doi.org/10.1242/dmm.021741Test

مصطلحات موضوعية: Animals, Basement Membrane/metabolism, Collagen Type IV/genetics, Endoplasmic Reticulum Stress, Humans, Kidney Glomerulus/metabolism, Kidney Tubules/metabolism, Mice, Mutation

الوصف: Collagen IV is a major component of basement membranes, and mutations in COL4A1, which encodes collagen IV alpha chain 1, cause a multisystemic disease encompassing cerebrovascular, eye and kidney defects. However, COL4A1 renal disease remains poorly characterized and its pathomolecular mechanisms are unknown. We show that Col4a1 mutations in mice cause hypotension and renal disease, including proteinuria and defects in Bowman's capsule and the glomerular basement membrane, indicating a role for Col4a1 in glomerular filtration. Impaired sodium reabsorption in the loop of Henle and distal nephron despite elevated aldosterone levels indicates that tubular defects contribute to the hypotension, highlighting a novel role for the basement membrane in vascular homeostasis by modulation of the tubular response to aldosterone. Col4a1 mutations also cause diabetes insipidus, whereby the tubular defects lead to polyuria associated with medullary atrophy and a subsequent reduction in the ability to upregulate aquaporin 2 and concentrate urine. Moreover, haematuria, haemorrhage and vascular basement membrane defects confirm an important vascular component. Interestingly, although structural and compositional basement membrane defects occurred in the glomerulus and Bowman's capsule, no tubular basement membrane defects were detected. By contrast, medullary atrophy was associated with chronic ER stress, providing evidence for cell-type-dependent molecular mechanisms of Col4a1 mutations. These data show that both basement membrane defects and ER stress contribute to Col4a1 renal disease, which has important implications for the development of treatment strategies for collagenopathies.

الإتاحة: https://doi.org/10.1242/dmm.021741Test
https://research.manchester.ac.uk/en/publications/f9110176-e284-46af-9162-685968049033Test

المساهمون: Sun Ha Lee, Sung Jin Moon, Jisun Paeng, Hye-Young Kang, Bo Young Nam, Seonghun Kim, Chan Ho Kim, Mi Jung Lee, Hyung Jung Oh, Jung Tak Park, Seung Hyeok Han, Tae-Hyun Yoo, Shin-Wook Kang, Kang, Hye Young, Kim, Seonghun, Kim, Chan Ho, Moon, Sung Jin, Park, Jung Tak, Oh, Hyung Jung, Yoo, Tae Hyun, Lee, Mi Jung, Lee, Sun Ha, Paeng, Ji Sun, Han, Seung Hyeok, Kang, Shin Wook

مصطلحات موضوعية: Animals, Apoptosis/drug effects, Apoptosis Regulatory Proteins/metabolism, Aspartic Acid/analogs & derivatives, Aspartic Acid/pharmacology, Caspase 3/metabolism, Caspase Inhibitors/pharmacology, Cells, Cultured, Diabetes Mellitus, Experimental/chemically induced, Gene Expression/drug effects, Hypertrophy/metabolism, Hypertrophy/pathology, Kidney Glomerulus/drug effects, Kidney Glomerulus/metabolism, Kidney Glomerulus/pathology, Male, Mice, Podocytes/drug effects, Podocytes/metabolism, Podocytes/pathology, Protein Kinase Inhibitors/pharmacology, Pyrimidines/pharmacology, Pyrroles/pharmacology, Rats, Sprague-Dawley, Receptor, Epidermal Growth Factor/antagonists & inhibitors, Epidermal Growth Factor/metabolism

الوصف: Podocyte hypertrophy and apoptosis are two hallmarks of diabetic glomeruli, but the sequence in which these processes occur remains a matter of debate. Here we investigated the effects of inhibiting hypertrophy on apoptosis, and vice versa, in both podocytes and glomeruli, under diabetic conditions. Hypertrophy and apoptosis were inhibited using an epidermal growth factor receptor inhibitor (PKI 166) and a pan-caspase inhibitor (zAsp-DCB), respectively. We observed significant increases in the protein expression of p27, p21, phospho-eukaryotic elongation factor 4E-binding protein 1, and phospho-p70 S6 ribosomal protein kinase, in both cultured podocytes exposed to high-glucose (HG) medium, and streptozotocin-induced diabetes mellitus (DM) rat glomeruli. These increases were significantly inhibited by PKI 166, but not by zAsp-DCB. In addition, the amount of protein per cell, the relative cell size, and the glomerular volume were all significantly increased under diabetic conditions, and these changes were also blocked by treatment with PKI 166, but not zAsp-DCB. Increased protein expression of cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase, together with increased Bax/Bcl-2 ratios, were also observed in HG-stimulated podocytes and DM glomeruli. Treatment with either zAsp-DCB or PKI 166 resulted in a significant attenuation of these effects. Both PKI 166 and zAsp-DCB also inhibited the increase in number of apoptotic cells, as assessed by Hoechst 33342 staining and TUNEL assay. Under diabetic conditions, inhibition of podocyte hypertrophy results in attenuated apoptosis, whereas blocking apoptosis has no effect on podocyte hypertrophy, suggesting that podocyte hypertrophy precedes apoptosis. ; open

وصف الملف: 1056~1071

العلاقة: APOPTOSIS; J00195; OAK-2015-01314; https://ir.ymlib.yonsei.ac.kr/handle/22282913/140474Test; http://link.springer.com/article/10.1007%2Fs10495-015-1134-0Test; T201502168; APOPTOSIS, Vol.20(8) : 1056-1071, 2015

الإتاحة: https://doi.org/10.1007/s10495-015-1134-0Test
https://ir.ymlib.yonsei.ac.kr/handle/22282913/140474Test

المساهمون: Se Jin Park, Eun-Mi Ahn, Tae-Sun Ha, Jae Il Shin, Shin, Jae Il

المصدر: T201402417.pdf

مصطلحات موضوعية: Actinin/metabolism, Animals, Cell Membrane/metabolism, Cell Nucleus/metabolism, Cells, Cultured, Diabetic Nephropathies/etiology, Diabetic Nephropathies/metabolism, Epithelial Cells/drug effects, Epithelial Cells/metabolism, Glucose, Glycation End Products, Advanced, Hyperglycemia/metabolism, Kidney Glomerulus/cytology, Kidney Glomerulus/metabolism, Mice, Models, Theoretical, Podocytes/drug effects, Podocytes/metabolism, RNA, Messenger/metabolism, Rats, beta Catenin/genetics, beta Catenin/metabolism, 棺-catenin, advanced glycation, endproducts, glomerular

الوصف: INTRODUCTION: The aim of our study was to determine whether beta-catenin, a subunit of the cadherin protein complex in the podocyte cytoskeleton, would be altered by hyperglycemia and advanced glycation endproducts (AGE) in glomerular epithelial cells and podocytes in vitro. MATERIALS AND METHODS: Rat glomerular epithelial cells and mouse podocytes on bovine serum albumin-coated or AGE-coated plates with normal (5 mM) and high (30 mM) glucose doses were cultured and examined for the distribution of bet;-catenin using confocal microscopy and changes in beta-catenin production by western blotting and reverse transcription-polymerase chain reaction, at 48 hours, 4 weeks, and 10 weeks. RESULTS: Immunofluorescent staining revealed that beta-catenin and alpha-actinin were colocalized around the cell membrane, and that beta-catenin staining was most intense along the capillary loops, but moved internally toward the inner actin filaments in the presence of AGE and hyperglycemia. In western blot analysis, AGE and hyperglycemia significantly decreased the amount of beta-catenin proteins by 31.5% at 48 hours, compared with normal control conditions (P = .01). The expression for beta-catenin mRNA in AGE and hyperglycemia was also decreased by 59.6% at 24 hours, compared with that of normal glucose conditions (P = .01). No significant changes were seen in the osmotic controls. CONCLUSIONS: Our results suggest that AGE and hyperglycemia may induce the cytoplasmic redistribution of beta-catenin and inhibit the production of beta-catenin at the transcriptional and posttranslational levels, which may result in the development of kidney dysfunction in diabetic conditions. ; open

وصف الملف: 299~309

العلاقة: IRANIAN JOURNAL OF KIDNEY DISEASES; J01189; OAK-2014-01402; https://ir.ymlib.yonsei.ac.kr/handle/22282913/99322Test; T201402417; IRANIAN JOURNAL OF KIDNEY DISEASES, Vol.8(4) : 299-309, 2014

الإتاحة: https://ir.ymlib.yonsei.ac.kr/handle/22282913/99322Test

المساهمون: Jisun Paeng, Jae Hyun Chang, Sun Ha Lee, Bo Young Nam, Hye-Young Kang, Seonghun Kim, Hyung Jung Oh, Jung Tak Park, Seung Hyeok Han, Tae-Hyun Yoo, Shin-Wook Kang, Han, Seung Hyeok, Kang, Shin Wook, Kang, Hye Young, Kim, Seonghun, Nam, Bo Young, Park, Jung Tak, Oh, Hyung Jung, Yoo, Tae Hyun, Lee, Sun Ha, Chang, Jae Hyun, Paeng, Ji Sun

مصطلحات موضوعية: Albuminuria/metabolism, Albuminuria/pathology, Animals, Apoptosis/drug effects, Apoptosis Regulatory Proteins/metabolism, Diabetes Mellitus, Experimental/metabolism, Experimental/pathology, Glucose/pharmacology, Glycogen Synthase Kinase 3/antagonists & inhibitors, Glycogen Synthase Kinase 3/metabolism, Glycogen Synthase Kinase 3 beta, Indoles/pharmacology, Kidney Glomerulus/metabolism, Kidney Glomerulus/pathology, Male, Oximes/pharmacology, Phosphorylation, Podocytes/drug effects, Podocytes/metabolism, Podocytes/pathology, Rats, Sprague-Dawley, Signal Transduction, Streptozocin, Tyrosine/metabolism, GSK-3棺, Diabetic nephropathy, Podocyte, Apoptosis

الوصف: Glycogen synthase kinase-3棺 (GSK-3棺) is involved in the pathogenesis of various kidney diseases. This study was undertaken to examine the changes in GSK-3棺 activity in podocytes under diabetic conditions and to elucidate the functional role of GSK-3棺 in podocyte apoptosis. In vivo, 32 rats were injected with either diluent (n = 16, C) or with streptozotocin intraperitoneally (n = 16, DM), and 8 rats from each group were treated with 6-bromoindirubin-3'-oxime (BIO) for 3 months. In vitro, immortalized mouse podocytes were exposed to 5.6 mM glucose or 30 mM glucose (HG) with or without 10 關M BIO. Western blot analysis and TUNEL or Hoechst 33342 staining were performed to identify apoptosis. Urinary albumin excretion was significantly higher in DM rats, and this increase was significantly abrogated in DM rats by BIO treatment. The protein expression of Tyr216-phospho-GSK-3棺 was significantly increased in DM glomeruli and in cultured podocytes exposed to HG. Western blot analysis revealed that the protein expression of Bax and active fragments of caspase-3 were significantly increased, whereas phospho-Akt, 棺-catenin, and Bcl-2 protein expression were significantly decreased in DM glomeruli and HG-stimulated podocytes. Apoptosis, determined by TUNEL assay and Hoechst 33342 staining, was also significantly increased in podocytes under diabetic conditions. The changes in the expression of apoptosis-related molecules and the increase in the number of apoptotic cells in DM glomeruli as well as in HG-stimulated podocytes were significantly ameliorated by BIO. These findings suggest that enhanced GSK-3棺 activity within podocytes under diabetic conditions is associated with podocyte loss in diabetic nephropathy. ; open

وصف الملف: 1678~1690

العلاقة: APOPTOSIS; J00195; OAK-2014-02515; https://ir.ymlib.yonsei.ac.kr/handle/22282913/138248Test; http://link.springer.com/article/10.1007%2Fs10495-014-1037-5Test; T201404185; APOPTOSIS, Vol.19(12) : 1678-1690, 2014

الإتاحة: https://doi.org/10.1007/s10495-014-1037-5Test
https://ir.ymlib.yonsei.ac.kr/handle/22282913/138248Test