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Sang-Ho Kwon, Sekyung Oh, Marisa Nacke, Keith E Mostov, Joshua H Lipschutz
Exosomes, 40-150 nm extracellular vesicles, transport biological macromolecules that mediate intercellular communications. While exosomes are known to originate from maturation of endosomes into multivesicular endosomes (MVEs; also known as multivesicular bodies, MVBs) with subsequent fusion of the MVEs with the plasma membrane, it remains unclear how cargos are selected for exosomal release. Using an inducible expression system for the exosome cargo protein GPRC5B and following its trafficking trajectory, we show here that newly synthesized GPRC5B protein accumulates in the Golgi complex prior to its release into exosomes...
October 20, 2016: Journal of Biological Chemistry
Hye-Young Park, Su-Bin Seong, Seo-Yun Min, Tae-Sun Ha
Angiotensin II (Ang II) works as a paracrine or autocrine cytokine agent to regulate renal functions and promotes podocytes dysfunction directly or indirectly, causing proteinuria. The glomerular slit diaphragm (SD) serves as a size-selective barrier and is linked to the actin-based cytoskeleton by adaptor proteins, including CD2-associated protein (CD2AP). Therefore, damages to CD2AP affect not only the function of the SD, but also directly disrupt the podocyte cytoskeleton, leading to proteinuria. In addition, CD2AP can facilitate the nephrin-induced phosphoinositide 3-kinase (PI3-K)/Akt signaling, which protects podocytes from apoptosis...
October 2016: International Journal of Biochemistry & Cell Biology
Maija Suvanto, Jaakko Patrakka, Timo Jahnukainen, Pia-Maria Sjöström, Matti Nuutinen, Pekka Arikoski, Janne Kataja, Marjo Kestilä, Hannu Jalanko
BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is a common cause of end-stage renal disease in children but also occurs as an adult-onset condition. In a subset of SRNS patients, pathogenic variants are found in genes coding for podocyte foot process proteins. The aim of this study was to define the role of pathogenic variants in Finnish patients with familial and sporadic SRNS. METHODS: We analyzed SRNS-related genes NPHS1, NPHS2, NEPH1, ACTN4, TRPC6, INF2, WT1, CD2AP, LAMB2, and PLCE1 for disease-causing variants using direct sequencing of exons and intron/exon boundaries in all members of a family with dominant SRNS with early onset and slow progression to end-stage renal disease...
August 29, 2016: Clinical and Experimental Nephrology
Jinn-Yang Chen, Deng-Yuan Jian, Chih-Chan Lien, Yu-Ting Lin, Ching-Heng Ting, Luen-Kui Chen, Ting-Chia Hsu, Hsuan-Min Huang, Yu-Ting Wu, Tse-Ting Kuan, Yu-Wen Chao, Liang-Yi Wu, Seng-Wong Huang, Chi-Chang Juan
Obesity is a risk factor that promotes progressive kidney disease. Studies have shown that an adipocytokine imbalance contributes to impaired renal function in humans and animals, but the underlying interplay between adipocytokines and renal injury remains to be elucidated. We aimed to investigate the mechanisms linking obesity to chronic kidney disease. We assessed renal function in high-fat diet (HF)-fed and normal diet-fed rats, and the effects of preadipocyte- and adipocyte-conditioned medium on cultured podocytes...
August 18, 2016: Journal of Endocrinology
Meijian Guan, Jun Ma, Jacob M Keaton, Latchezar Dimitrov, Poorva Mudgal, Mary Stromberg, Jason A Bonomo, Pamela J Hicks, Barry I Freedman, Donald W Bowden, Maggie C Y Ng
African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD) compared to European Americans. Genome-wide association studies have identified variants associated with diabetic and non-diabetic kidney diseases. Nephropathy loci, including SLC7A9, UMOD, and SHROOM3, have been implicated in the maintenance of normal glomerular and renal tubular structure and function. Herein, 47 genes important in podocyte, glomerular basement membrane, mesangial cell, mesangial matrix, renal tubular cell, and renal interstitium structure were examined for association with type 2 diabetes (T2D)-attributed ESKD in AAs...
November 2016: Human Genetics
S Kuusela, H Wang, A A Wasik, H Suleiman, S Lehtonen
Inappropriate activation of the Wnt/β-catenin pathway has been indicated in podocyte dysfunction and injury, and shown to contribute to the development and progression of nephropathy. Tankyrases, multifunctional poly(ADP-ribose) polymerase (PARP) superfamily members with features of both signaling and cytoskeletal proteins, antagonize Wnt/β-catenin signaling. We found that tankyrases interact with CD2-associated protein (CD2AP), a protein essential for kidney ultrafiltration as CD2AP-knockout (CD2AP-/-) mice die of kidney failure at the age of 6-7 weeks...
2016: Cell Death & Disease
Leopoldo Raij, Runxia Tian, Jenny S Wong, John Cijiang He, Kirk N Campbell
Podocytes are the key target for injury in proteinuric glomerular diseases that result in podocyte loss, progressive focal segmental glomerular sclerosis (FSGS) and renal failure. Current evidence suggests that the initiation of podocyte injury and associated proteinuria can be separated from factors that drive and maintain these pathogenic processes leading to FSGS. In nephrotic urine aberrant glomerular filtration of Plasminogen (Plg) is activated to the biologically active serine protease Plasmin by urokinase type plasminogen activator (uPA)...
June 22, 2016: American Journal of Physiology. Renal Physiology
Celeste Sassi, Michael A Nalls, Perry G Ridge, Jesse R Gibbs, Jinhui Ding, Michelle K Lupton, Claire Troakes, Katie Lunnon, Safa Al-Sarraj, Kristelle S Brown, Christopher Medway, Naomi Clement, Jenny Lord, James Turton, Jose Bras, Maria R Almeida, Henne Holstege, Eva Louwersheimer, Wiesje M van der Flier, Philip Scheltens, John C Van Swieten, Isabel Santana, Catarina Oliveira, Kevin Morgan, John F Powell, John S Kauwe, Carlos Cruchaga, Alison M Goate, Andrew B Singleton, Rita Guerreiro, John Hardy
Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer's disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease...
October 2016: Neurobiology of Aging
Na Wang, Ri-bao Wei, Ping Li, Qing-ping Li, Xi Yang, Yue Yang, Meng-jie Huang, Rui Wang, Zhong Yin, Yang Lv, Xiang-mei Chen
OBJECTIVE: The study aimed to evaluate the effects of oral administration of irbesartan in adriamycin-induced nephropathy considering laboratory changes, kidney histology, and expression of proteins related to slit diaphragm and cytoskeleton of the podocyte. METHODS: The animals were divided into control, model, methylprednisolone (MP), and irbesartan groups. The 24-hour urinary protein and biochemical indicators were determined, and renal pathological changes were observed...
April 2016: Journal of the Renin-angiotensin-aldosterone System: JRAAS
Roger N Rosenberg, Doris Lambracht-Washington, Gang Yu, Weiming Xia
IMPORTANCE: To provide a comprehensive review of knowledge of the genomics of Alzheimer disease (AD) and DNA amyloid β 42 (Aβ42) vaccination as a potential therapy. OBSERVATIONS: Genotype-phenotype correlations of AD are presented to provide a comprehensive appreciation of the spectrum of disease causation. Alzheimer disease is caused in part by the overproduction and lack of clearance of Aβ protein. Oligomer Aβ, the most toxic species of Aβ, causes direct injury to neurons, accompanied by enhanced neuroinflammation, astrocytosis and gliosis, and eventually neuronal loss...
July 1, 2016: JAMA Neurology
Ekaterina A Ivanova, Fanny O Arcolino, Mohamed A Elmonem, Maria P Rastaldi, Laura Giardino, Elisabeth M Cornelissen, Lambertus P van den Heuvel, Elena N Levtchenko
The involvement of the glomerulus in the pathogenesis of cystinosis, caused by loss-of-function mutations in cystinosin (CTNS, 17p13), is a matter of controversy. Although patients with cystinosis demonstrate glomerular lesions and high-molecular-weight proteinuria starting from an early age, a mouse model of cystinosis develops only signs of proximal tubular dysfunction. Here we studied podocyte damage in patients with cystinosis by analyzing urinary podocyte excretion and by in vitro studies of podocytes deficient in cystinosin...
May 2016: Kidney International
Benjamin J Harrison, Gayathri Venkat, James L Lamb, Tom H Hutson, Cassa Drury, Kristofer K Rau, Mary Barlett Bunge, Lorne M Mendell, Fred H Gage, Richard D Johnson, Caitlin E Hill, Eric C Rouchka, Lawrence D F Moon, Jeffrey C Petruska
UNLABELLED: Growth of intact axons of noninjured neurons, often termed collateral sprouting, contributes to both adaptive and pathological plasticity in the adult nervous system, but the intracellular factors controlling this growth are largely unknown. An automated functional assay of genes regulated in sensory neurons from the rat in vivo spared dermatome model of collateral sprouting identified the adaptor protein CD2-associated protein (CD2AP; human CMS) as a positive regulator of axon growth...
April 13, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Andreas Lazaris, Kristy S Hwang, Naira Goukasian, Leslie M Ramirez, Jennifer Eastman, Anna E Blanken, Edmond Teng, Karen Gylys, Greg Cole, Andrew J Saykin, Leslie M Shaw, John Q Trojanowski, William J Jagust, Michael W Weiner, Liana G Apostolova
OBJECTIVE: We investigated the association between apoE protein plasma levels and brain amyloidosis and the effect of the top 10 Alzheimer disease (AD) risk genes on this association. METHODS: Our dataset consisted of 18 AD, 52 mild cognitive impairment, and 3 cognitively normal Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) participants with available [(11)C]-Pittsburgh compound B (PiB) and peripheral blood protein data. We used cortical pattern matching to study associations between plasma apoE and cortical PiB binding and the effect of carrier status for the top 10 AD risk genes...
October 2015: Neurology. Genetics
Kamel Laribi, Nathalie Denizon, Anne Besançon, Jonathan Farhi, Pierre Lemaire, Jeremy Sandrini, Catherine Truong, Habib Ghnaya, Alix Baugier de Materre
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with an aggressive clinical course. It is grouped with acute myeloid leukemia-related precursor neoplasms in the 2008 World Health Organization classification. Most patients with BPDCN have skin lesions at diagnosis and subsequent or simultaneous involvement of the bone marrow, peripheral blood, and lymph nodes. Patients usually respond to initial chemotherapy but often relapse. Stem cell transplantation may improve survival...
August 2016: Biology of Blood and Marrow Transplantation
Jasmine Nettiksimmons, Gregory Tranah, Daniel S Evans, Jennifer S Yokoyama, Kristine Yaffe
Single nucleotide polymorphisms (SNPs) in and near ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, complement receptor 1 (CR1), EPHA1, EXOC3L2, FERMT2, HLA cluster (DRB5-DQA), INPP5D, MEF2C, MS4A cluster (MS4A3-MS4A6E), NME8, PICALM, PTK2B, SLC24A4, SORL1, and ZCWPW1 have been associated with Alzheimer's disease (AD) in large meta-analyses. We aimed to determine whether established AD-associated genes are associated with longitudinal cognitive decline by examining aggregate variation across these gene regions...
April 2016: Age (2005-)
Dmitry Tsvetkov, Michael Hohmann, Yoland Marie Anistan, Marwan Mannaa, Christian Harteneck, Birgit Rudolph, Maik Gollasch
Mutations in CD2-associated protein (CD2AP) have been identified in patients with focal segmental glomerulosclerosis (FSGS); however, reports of CD2AP mutations remain scarce. We performed Sanger sequencing in a patient with steroid-resistant FSGS and identified a heterozygous CD2AP mutation (p.T374A, c.1120 A > G). Our patient displayed mild cognitive decline, a phenotypic characteristic not previously associated with CD2AP-associated FSGS. His proteinuria was remarkably reduced by treatment with cyclosporine A...
2016: Clinical Medicine Insights. Case Reports
Keisuke Sugimoto, Tomoki Miyazawa, Takuji Enya, Kouhei Miyazaki, Mitsuru Okada, Tsukasa Takemura
BACKGROUND: Cyclosporine A (CsA) is used globally as an immunosuppressant for the treatment of immune-mediated nephrotic syndrome (NS). However, its long-term use causes nephrotoxicity characterized by tubulointerstitial injury and glomerulosclerosis. The present study aimed to investigate the associations between histomorphological findings and immunohistological expression of Cathepsin L (CatL) and CD2-associated protein (CD2AP) in patients with NS mediated with CsA. METHODS: A total of 18 patients with child-onset NS were divided into two groups after treatment with CsA for 2 years (group A; n = 10) and more than 4 years (group B; n = 8), respectively...
March 14, 2016: Clinical and Experimental Nephrology
Erdem Varol, Aristeidis Sotiras, Christos Davatzikos
Multivariate pattern analysis techniques have been increasingly used over the past decade to derive highly sensitive and specific biomarkers of diseases on an individual basis. The driving assumption behind the vast majority of the existing methodologies is that a single imaging pattern can distinguish between healthy and diseased populations, or between two subgroups of patients (e.g., progressors vs. non-progressors). This assumption effectively ignores the ample evidence for the heterogeneous nature of brain diseases...
February 23, 2016: NeuroImage
Yu-Ping Huang, Ling-Zhi Qiu, Guo-Ping Zhou
CD2-associated protein (CD2AP) serves as a slit diaphragm (SD) protein and plays essential roles in maintaining podocyte integrity and reducing proteinuria. MicroRNAs (miRNAs) are novel regulators of gene expression. Podocyte-specific loss of miRNAs would lead to significant proteinuria. Here, we report new evidence in which miRNAs may function to suppress CD2AP expression through a transcriptional way. By scanning human CD2AP promoter in silico for sequences complementary to known miRNAs, we chose miR-939, miR-148b*, miR-191*, miR-638 as four candidates and transfected them into HEK-293T cells...
2016: Renal Failure
Hannah W R Yasin, Samuel H van Rensburg, Christina E Feiler, Ruth I Johnson
Epithelia are essential barrier tissues that must be appropriately maintained for their correct function. To achieve this a plethora of protein interactions regulate epithelial cell number, structure and adhesion, and differentiation. Here we show that Cindr (the Drosophila Cin85 and Cd2ap ortholog) is required to maintain epithelial integrity. Reducing Cindr triggered cell delamination and movement. Most delaminating cells died. These behaviors were consistent with JNK activation previously associated with loss of epithelial integrity in response to ectopic oncogene activity...
February 15, 2016: Developmental Biology
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