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https://www.readbyqxmd.com/read/28208054/high-glucose-induced-hypomethylation-promotes-binding-of-sp-1-to-myo-inositol-oxygenase-implication-in-the-pathobiology-of-diabetic-tubulopathy
#1
Isha Sharma, Rajesh K Dutta, Neel K Singh, Yashpal S Kanwar
The catabolic enzyme myo-inositol oxygenase (MIOX) is expressed in proximal tubules and up-regulated in the diabetic state. Previously, we reported its transcriptional and translation regulation by high glucose (HG), osmolytes, and fatty acids. However, its epigenetic regulation is unknown. Bisulfite sequencing revealed that both human and mouse MIOX promoters, enriched with CpG sites, are hypomethylated and unmethylated under HG ambience and hyperglycemic states associated with increased MIOX expression. Eletrophoretic mobility shift assays revealed increased binding of unmethylated oligos with nucleoproteins of cells maintained under HG...
February 13, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28149671/macrophage-tgf-%C3%AE-1-and-the-proapoptotic-extracellular-matrix-protein-bigh3-induce-renal-cell-apoptosis-in-prediabetic-and-diabetic-conditions
#2
Robert J Moritz, Richard G LeBaron, Clyde F Phelix, Rajesha Rupaimoole, Hong Seok Kim, Andrew Tsin, Reto Asmis
Metabolically stressed kidney is in part characterized by infiltrating macrophages and macrophage-derived TGF-β1 that promote the synthesis of various ECM molecules. TGF-β1 strongly enhances the expression of the gene TGFBI that encodes a cell-adhesion class, proapoptotic ECM protein called BIGH3. We hypothesized that in a diabetic environment a relationship between infiltrating macrophages, macrophage-derived TGF-β1, and BIGH3 protein promotes renal cell death. To investigate this hypothesis, we used our mouse model of diabetic complications...
July 2016: International Journal of Clinical Medicine
https://www.readbyqxmd.com/read/28127848/mir-30c-protects-diabetic-nephropathy-by-suppressing-epithelial-to-mesenchymal-transition-in-db-db-mice
#3
Yanru Zhao, Zhongwei Yin, Huaping Li, Jiahui Fan, Shenglan Yang, Chen Chen, Dao Wen Wang
Epithelial-to-mesenchymal transition (EMT) plays a significant role in tubulointerstitial fibrosis, which is a hallmark of diabetic nephropathy. Thus, identifying the mechanisms of EMT activation could be meaningful. In this study, loss of miR-30c accompanied with increased EMT was observed in renal tubules of db/db mice and cultured HK2 cells exposed to high glucose. To further explore the roles of miR-30c in EMT and tubulointerstitial fibrosis, recombinant adeno-associated viral vector was applied to manipulate the expression of miR-30c...
January 27, 2017: Aging Cell
https://www.readbyqxmd.com/read/28077323/high-glucose-down-regulates-microrna-181a-5p-to-increase-pro-fibrotic-gene-expression-by-targeting-early-growth-response-factor-1-in-hk-2-cells
#4
Ping Xu, Mei-Ping Guan, Jian-Gang Bi, Dan Wang, Zong-Ji Zheng, Yao-Ming Xue
Tubulointerstitial fibrosis (TIF) plays an important role in the progression of renal fibrosis in diabetic nephropathy (DN). Accumulating evidence supports a crucial effect of early growth response factor 1 (Egr1) on renal fibrosis in DN, but the underlying mechanisms are not entirely clear. Here, we explored the aggravating role of Egr1 and identified microRNA-181a-5p (miR-181a-5p) as an upstream regulator of Egr1 in TIF of DN. We demonstrated that overexpression of Egr1 enhanced, whereas small interfering RNA targeting Egr1 decreased the expressions of transforming growth factor β1 (TGF-β1) and fibrosis-related genes including fibronectin and collagen I in human proximal tubule cell line (HK-2) cells...
February 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28064277/smad2-phosphorylation-in-diabetic-kidney-tubule-epithelial-cells-is-associated-with-modulation-of-several-transforming-growth-factor-%C3%AE-family-members
#5
Lise Høj Thomsen, Morten Fog-Tonnesen, Lisbeth Nielsen Fink, Jenny Norlin, Amaya García de Vinuesa, Troels Krarup Hansen, Emile de Heer, Peter Ten Dijke, Alexander Rosendahl
BACKGROUND: The role of transforming growth factor-β (TGF-β) has recently gained much attention in diabetic nephropathy and kidney fibrosis. In this study, we extend this to an assessment of transcriptional regulation of the entire TGF-β superfamily in kidneys from diabetic vs. healthy mice. In order to study the translation between mouse model and patients, we evaluated the signature of phosphorylated Sma- and Mad-related protein 2 (pSmad2), as molecular marker of TGF-β/activin activity, in the kidneys of streptozotocin (STZ)-treated mice compared to that of type 1 diabetes (T1D) patients...
January 7, 2017: Nephron
https://www.readbyqxmd.com/read/27916082/-effects-of-ammonium-pyrrolidine-dithiocarbamate-pdtc-on-osteopontin-expression-and-autophagy-in-tubular-cells-in-streptozotocin-induced-diabetic-nephropathy-rat
#6
S Gao, J Y Jia, T K Yan, Y M Yu, W Y Shang, L Wei, Z F Zheng, P Fang, B C Chang, S Lin
Objective: To investigate the effects of ammonium pyrrolidine dithiocarbamate (PDTC) on tubulointerstitial inflammatory molecules and autophagy in diabetic nephropathy (DN) rats. Methods: Twenty-four male Sprague-Dawley rats were assigned to DN group (n=6) and DN+ PDTC group (n=6, PDTC, ip, 100 mg·kg(-1)·d(-1)), all received streptozotocin (STZ) 60 mg/kg intraperitoneally, and the other 12 rats were randomly divided into control group (n=6) and PDTC group (n=6). At the end of 12 weeks, after serum creatine (Scr) and 24-hour urinary protein were determined, rats were sacrificed to determined the renal pathological damages and the changes of nuclear factor (NF)-κB p65, p62, osteopontin (OPN), microtubule associated protein 1 light chain 3 (LC3)-Ⅱ/LC3-Ⅰ, nuclear p-NF-κB p65 by immunohistological stainning and Western blot, and ultrastructural changes of autophagic process was observed by electron microscopy (EM)...
November 29, 2016: Zhonghua Yi Xue za Zhi [Chinese medical journal]
https://www.readbyqxmd.com/read/27849017/elmo1-protects-renal-structure-and-ultrafiltration-in-kidney-development-and-under-diabetic-conditions
#7
Krishna Rakesh Sharma, Karl Heckler, Sandra J Stoll, Jan-Luuk Hillebrands, Katharina Kynast, Esther Herpel, Stefan Porubsky, Marlies Elger, Boris Hadaschik, Karen Bieback, Hans-Peter Hammes, Peter P Nawroth, Jens Kroll
Engulfment and cell motility 1 (ELMO1) functions as a guanine exchange factor for Rac1 and was recently found to protect endothelial cells from apoptosis. Genome wide association studies suggest that polymorphisms within human elmo1 act as a potential contributing factor for the development of diabetic nephropathy. Yet, the function of ELMO1 with respect to the glomerulus and how this protein contributes to renal pathology was unknown. Thus, this study aimed to identify the role played by ELMO1 in renal development in zebrafish, under hyperglycaemic conditions, and in diabetic nephropathy patients...
November 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27798458/the-angiotensin-type-2-receptor-and-the-kidney
#8
Antonio A B Peluso, Robson A S Santos, Thomas Unger, U Muscha Steckelings
PURPOSE OF REVIEW: Angiotensin II is a main regulator of kidney function. Renal actions mediated by the angiotensin AT1 receptor have been well known for many years. In contrast, several details of angiotensin AT2 receptor actions in kidney physiology and pathophysiology were only described very recently. These findings are reviewed in this article. RECENT FINDINGS: Regarding the role of the angiotensin AT2 receptor in kidney physiology, a major recent finding was that the AT2 receptor-mediated inhibition of Na-H exchanger-3 and Na/K-ATPase in the renal proximal tubules is caused by internalisation of these transporters, thus reducing reabsorption and increasing natriuresis/diuresis...
January 2017: Current Opinion in Nephrology and Hypertension
https://www.readbyqxmd.com/read/27777973/systems-biology-analysis-reveals-role-of-mdm2-in-diabetic-nephropathy
#9
Rintaro Saito, Anaïs Rocanin-Arjo, Young-Hyun You, Manjula Darshi, Benjamin Van Espen, Satoshi Miyamoto, Jessica Pham, Minya Pu, Simone Romoli, Loki Natarajan, Wenjun Ju, Matthias Kretzler, Robert Nelson, Keiichiro Ono, Dana Thomasova, Shrikant R Mulay, Trey Ideker, Vivette D'Agati, Ergin Beyret, Juan Carlos Izpisua Belmonte, Hans Joachim Anders, Kumar Sharma
To derive new insights in diabetic complications, we integrated publicly available human protein-protein interaction (PPI) networks with global metabolic networks using metabolomic data from patients with diabetic nephropathy. We focused on the participating proteins in the network that were computationally predicted to connect the urine metabolites. MDM2 had the highest significant number of PPI connections. As validation, significant downregulation of MDM2 gene expression was found in both glomerular and tubulointerstitial compartments of kidney biopsy tissue from 2 independent cohorts of patients with diabetic nephropathy...
October 20, 2016: JCI Insight
https://www.readbyqxmd.com/read/27771693/kidney-injury-marker-1-and-neutrophil-gelatinase-associated-lipocalin-in-chronic-kidney-disease
#10
Esmeralda Castillo-Rodriguez, Raul Fernandez-Prado, Catalina Martin-Cleary, Maria Soledad Pizarro-Sánchez, Maria Dolores Sanchez-Niño, Ana Belen Sanz, Beatriz Fernandez-Fernandez, Alberto Ortiz
The current categorization of chronic kidney disease (CKD) is based on biomarkers of the glomerular function (estimated glomerular filtration rate, eGFR) and injury (urinary albumin creatinine ratio, UACR) and provides information on the risk of death and of progression of kidney disease. However, there are gaps in knowledge regarding the risk stratification of elderly patients with eGFR 45-60 ml/min/1.73 m2 and of younger patients with higher eGFR but physiological albuminuria. In this regard, most of the kidney cell mass is composed of tubules...
October 22, 2016: Nephron
https://www.readbyqxmd.com/read/27757071/n-glycosylation-proteome-enrichment-analysis-in-kidney-reveals-differences-between-diabetic-mouse-models
#11
Leena Liljedahl, Maiken Højgaard Pedersen, Jenny Norlin, James N McGuire, Peter James
BACKGROUND: Diabetic nephropathy (DN) is a late complication in both type 1 diabetes mellitus (T1DM) and T2DM. Already at an early stage of DN morphological changes occur at the cell surface and in the extracellular matrix where the majority of the proteins carry N-linked glycosylations. These glycosylated proteins are highly important in cell adhesion and cell-matrix processes but not much is known about how they change in DN or whether the distinct etiology of T1DM and T2DM could have an effect on their abundances...
2016: Clinical Proteomics
https://www.readbyqxmd.com/read/27754252/os-36-03-e-box-cpg-hypomethylation-of-nmn-producing-enzyme-nampt-in-proximal-tubules-enables-constant-supply-of-nmn-from-tubules-to-glomeruli-which-is-disrupted-in-diabetic-nephropathy
#12
Hirokazu Muraoka, Kazuhiro Hasegawa, Shu Wakino
OBJECTIVE: Nicotinamide phosphoribosyltransferase (Nampt) cooperates with a longevity gene, Sirt1, to exert the potentiation of stress resistance. We have reported that the high expression level of Nampt in PTs contributes to the sufficient supply of NMN to glomeruli. We also showed that downregulation of Nampt and NMN in PT in DN leads to glomerular damages (Nature Medicine 2013). However, the regulation mechanisms of Nampt expression remain unknown. DESIGN AND METHOD: We investigated how Nampt expression is consistently retained at high levels in PTs under normal conditions and how Nampt levels are decreased in DN...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27669287/tauroursodeoxycholic-acid-attenuates-renal-tubular-injury-in-a-mouse-model-of-type-2-diabetes
#13
Jing Zhang, Ying Fan, Chuchu Zeng, Li He, Niansong Wang
Renal tubular injury is a critical factor in the pathogenesis of diabetic nephropathy (DN). Endoplasmic reticulum (ER) stress is involved in diabetic nephropathy. Tauroursodeoxycholic acid (TUDCA) is an effective inhibitor of ER stress. Here, we investigated the role of TUDCA in the progression of tubular injury in DN. For eight weeks, being treated with TUDCA at 250 mg/kg intraperitoneal injection (i.p.) twice a day, diabetic db/db mice had significantly reduced blood glucose, albuminuria and attenuated renal histopathology...
September 22, 2016: Nutrients
https://www.readbyqxmd.com/read/27643217/os-36-03-e-box-cpg-hypomethylation-of-nmn-producing-enzyme-nampt-in-proximal-tubules-enables-constant-supply-of-nmn-from-tubules-to-glomeruli-which-is-disrupted-in-diabetic-nephropathy
#14
Hirokazu Muraoka, Kazuhiro Hasegawa, Shu Wakino
OBJECTIVE: Nicotinamide phosphoribosyltransferase (Nampt) cooperates with a longevity gene, Sirt1, to exert the potentiation of stress resistance. We have reported that the high expression level of Nampt in PTs contributes to the sufficient supply of NMN to glomeruli. We also showed that downregulation of Nampt and NMN in PT in DN leads to glomerular damages (Nature Medicine 2013). However, the regulation mechanisms of Nampt expression remain unknown. DESIGN AND METHOD: We investigated how Nampt expression is consistently retained at high levels in PTs under normal conditions and how Nampt levels are decreased in DN...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27591880/effect-of-linagliptin-on-structural-changes-in-the-kidney-in-experimental-type-2-diabetes-mellitus
#15
Yu S Gavrilova, N P Bgatova, V V Klimontov, I Yu Ischenko, S V Michurina, N E Myakina, E L Zavyalov
Effect of the dipeptidyl peptidase-4 inhibitor linagliptin on structural manifestations of diabetic nephropathy was studied in BKS.Cg-Dock7m+/+Leprdb/J mice (experimental model of type 2 diabetes mellitus). Linagliptin (10 mg/kg per day) or vehicle was administered by gavage over 8 weeks. Mesangial expansion, thickening of the basement membrane in glomerular capillaries and proximal tubules, and retraction of cytopodia were less pronounced in mice receiving linagliptin. The protective effect of linagliptin on the kidney structure was not associated with its hypoglycemic action...
August 2016: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/27470548/sirt1-activator-ameliorates-the-renal-tubular-injury-induced-by-hyperglycemia-in-vivo-and-in-vitro-via-inhibiting-apoptosis
#16
Xue-Ling Wang, Li-Yan Wu, Long Zhao, Li-Na Sun, Hai-Ying Liu, Gang Liu, Guang-Ju Guan
We aimed to explore the role of SIRT1 in apoptosis in human kidney proximal tubule epithelial (HK-2) cells, and to determine whether resveratrol (RSV, a SIRT1 activator) could ameliorate apoptosis in rats with streptozotocin-induced diabetes mellitus (DM) and/or in high glucose (HG, 30mM) - stimulated HK-2 cells. Rats were distributed randomly into three groups: 1) control group, 2) DM group, and 3) DM with RSV group (DM+RSV; rats treated with 30mg/kg/d of RSV for 16 weeks). The physical, biochemical, and morphological parameters were then examined...
October 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27440829/sglt2-inhibitors-and-the-diabetic-kidney
#17
Paola Fioretto, Alberto Zambon, Marco Rossato, Luca Busetto, Roberto Vettor
Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects...
August 2016: Diabetes Care
https://www.readbyqxmd.com/read/27388219/nmda-receptors-as-potential-therapeutic-targets-in-diabetic-nephropathy-increased-renal-nmda-receptor-subunit-expression-in-akita-mice-and-reduced-nephropathy-following-sustained-treatment-with-memantine-or-mk-801
#18
Hila Roshanravan, Eun Young Kim, Stuart E Dryer
N-methyl-d-aspartate (NMDA) receptors are expressed throughout the kidney, and the abundance of these receptors and some of their endogenous agonists are increased in diabetes. Moreover, sustained activation of podocyte NMDA receptors induces Ca(2+) influx, oxidative stress, loss of slit diaphragm proteins, and apoptosis. We observed that NMDA receptor subunits and their transcripts are increased in podocytes and mesangial cells cultured in elevated glucose compared with controls. A similar increase in NMDA subunits, especially NR1, NR2A, and NR2C, was observed in glomeruli and tubules of Akita mice...
October 2016: Diabetes
https://www.readbyqxmd.com/read/27382987/increase-of-total-nephron-albumin-filtration-and-reabsorption-in-diabetic-nephropathy
#19
Keita P Mori, Hideki Yokoi, Masato Kasahara, Hirotaka Imamaki, Akira Ishii, Takashige Kuwabara, Kenichi Koga, Yukiko Kato, Naohiro Toda, Shoko Ohno, Koichiro Kuwahara, Tomomi Endo, Kazuwa Nakao, Motoko Yanagita, Masashi Mukoyama, Kiyoshi Mori
The amount of albumin filtered through the glomeruli and reabsorbed at the proximal tubules in normal and in diabetic kidneys is debated. The megalin/cubilin complex mediates protein reabsorption, but genetic knockout of megalin is perinatally lethal. To overcome current technical problems, we generated a drug-inducible megalin-knockout mouse line, megalin(lox/lox);Ndrg1-CreER(T2) (iMegKO), in which megalin expression can be shut off at any time by administration of tamoxifen (Tam). Tam administration in adult iMegKO mice decreased the expression of renal megalin protein by 92% compared with that in wild-type C57BL/6J mice and almost completely abrogated renal reabsorption of intravenously injected retinol-binding protein...
January 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27367912/cannabinoid-receptors-in-the-kidney
#20
Deanne H Hryciw, Andrew J McAinch
PURPOSE OF REVIEW: The endocannabinoid system modulates cell signaling targets that are essential for energy homeostasis. Endocannabinoids bind to G protein-coupled receptors in the central nervous system and periphery, including the kidney. Modulation of cannabinoid receptor 1 (CB1) and CB2 activity in the kidney in diabetes and obesity has been identified as potential therapeutic target to reduce albuminuria and renal fibrosis. This review will highlight the results of recent studies that have identified a role for CB1 and CB2 in normal and pathological renal conditions...
September 2016: Current Opinion in Nephrology and Hypertension
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