Management of Steroid-Resistant Nephrotic Syndrome in Children and Adolescents

Total Page:16

File Type:pdf, Size:1020Kb

Management of Steroid-Resistant Nephrotic Syndrome in Children and Adolescents Review Management of steroid-resistant nephrotic syndrome in children and adolescents Kjell Tullus, Hazel Webb, Arvind Bagga More than 85% of children and adolescents (majority between 1–12 years old) with idiopathic nephrotic syndrome Lancet Child Adolesc Health 2018 show complete remission of proteinuria following daily treatment with corticosteroids. Patients who do not show Published Online remission after 4 weeks’ treatment with daily prednisolone are considered to have steroid-resistant nephrotic October 17, 2018 syndrome (SRNS). Renal histology in most patients shows presence of focal segmental glomerulosclerosis, minimal http://dx.doi.org/10.1016/ S2352-4642(18)30283-9 change disease, and (rarely) mesangioproliferative glomerulonephritis. A third of patients with SRNS show mutations Nephrology Unit, Great in one of the key podocyte genes. The remaining cases of SRNS are probably caused by an undefined circulating Ormond Street Hospital for factor. Treatment with calcineurin inhibitors (ciclosporin and tacrolimus) is the standard of care for patients with Children, Great Ormond Street, non-genetic SRNS, and approximately 70% of patients achieve a complete or partial remission and show satisfactory London, UK (K Tullus MD, long-term outcome. Additional treatment with drugs that inhibit the renin–angiotensin axis is recommended for H Webb BSc) andDivision of Nephrology, Indian Council of hypertension and for reducing remaining proteinuria. Patients with SRNS who do not respond to treatment with Medical Research Advanced calcineurin inhibitors or other immunosuppressive drugs can show declining kidney function and are at risk for end- Center for Research in stage renal failure. Approximately a third of those who undergo renal transplantation show recurrent focal segmental Nephrology, All India Institute glomerulosclerosis in the allograft and often respond to combined treatment with plasma exchange, rituximab, and of Medical Sciences, New Delhi, India (Prof A Bagga MD) intensified immunosuppression. Correspondence to: Dr Kjell Tullus, Nephrology Unit, Introduction prednisolone at a dose of 60 mg/m² daily for 4 weeks. Great Ormond Street Hospital for Nephrotic syndrome is diagnosed based on a triad of Others recommend treatment for 8 weeks.2–4 Several Children, Great Ormond Street, symptoms: severe proteinuria (>1 g/m² per day), centres, including the Great Ormond Street Hospital for London WC1N 3JH, UK [email protected] hypoalbuminaemia (albumin <2·5 g/dL), and oedema. Children, London, UK, administer three intra venous Most children older than 1 year (generally until 12 years pulses of methylprednisolone (500 mg/m²) before old) are diagnosed with idiopathic nephrotic syndrome regarding patients as resistant.5 Steroid resistance most based on these features and little else. A secondary cause often occurs during initial treatment with prednisolone (eg, systemic lupus erythematosus and Henoch- (initial resistance), but can also occur during treatment Schönlein purpura) is rare. for a relapse, in a patient who had previously responded Idiopathic nephrotic syndrome presents as an acute to treatment with steroids or with a second-line drug disease, with substantial proteinuria and increasing (late resistance). Steroid resistance is an important deter- oedema. A smaller proportion of patients have a slower minant of future risk for end-stage renal disease. and more atypical onset, sometimes over several months or even years. Atypical features include onset in infancy or adolescence, symptoms suggestive of an inflam- Key messages matory kidney disease, renal failure, hypertension, and • About 10–15% of children with idiopathic nephrotic syndrome who do not show macroscopic haematuria. complete remission of proteinuria following 4 weeks’ treatment with corticosteroids More than 85% of patients with idiopathic nephrotic are considered to have steroid-resistant nephrotic syndrome syndrome respond (ie, complete remission of proteinuria • For 30% of patients with steroid-resistant nephrotic syndrome, the condition results and normal serum albumin) following treatment with from a genetic cause; for the remainder, the disease is probably caused by a circulating 1 prednisolone. Response to prednisolone is an important factor prognostic indicator for survival of kidney function. • Renal histology shows minimal change disease and focal segmental glomerulosclerosis Although many patients with steroid-sensitive nephrotic (FSGS) in most patients syndrome have frequent relapses or steroid dependence, • Approximately 50–70% of patients with steroid resistance show complete or partial the long-term outlook for kidney function is favourable. remission following treatment with a calcineurin inhibitor (either ciclosporin or The main long-term problem in these patients is the risk tacrolimus) of side-effects from prolonged treatment with cortico- • Although additional treatment with mycophenolate mofetil or rituximab is steroids and other immuno suppressive medications. considered in children who are resistant to treatment with steroids and calcineurin Patients who do not respond to prednisolone are inhibitors, their efficacy to induce remission is low considered to have steroid-resistant nephrotic syndrome • Patients with a genetic FSGS or those who do not show complete or partial remission (SRNS). The medical community has not yet reached a following treatment with calcineurin inhibitors have high risk of end-stage renal failure consensus regarding the length of time prednisolone • Patients with late resistance and absence of a genetic cause show high risk of recurrent should be given before regarding a patient as steroid FSGS in the renal allograft resistant. We recommend that steroid resistance should • Intensification of treatment with ciclosporin or tacrolimus, and combined treatment be considered in patients who do not show complete with rituximab and plasma exchange might prevent or treat recurrent FSGS effectively remission of proteinuria despite treatment with www.thelancet.com/child-adolescent Published online October 17, 2018 http://dx.doi.org/10.1016/S2352-4642(18)30283-9 1 Review Congenital nephrotic syndrome refers to infants with slit diaphragm (NPHS1, NPHS2, CD2AP, and PLCE1); onset of nephrotic syndrome before 3 months of age. cytoskeleton (ACTN4, MHY9, MYO1E, INF2, and actin Most of these patients have mutations involving the regulatory genes); glomerular basement membrane and podocyte proteins (nephrin, podocin, and WT1) and do matrix proteins (LAMB2, ITGA3, and COL4A3–5); not respond to treatment with steroids and other mitochondrial proteins (COQ2, COQ6, and ADCK4); medications. The course of illness is progressive and nuclear proteins (WT1, LMX1B, NUP93, NUP107, most patients require renal replacement treatment in the NUP205, and SMARCAL1); and other intracellular first decade. We have not included the clinical manage- proteins (TRPC6, SCARB2, APOL1, DGKE, CUBN, ment of these children in this Review. and GAPVD1) with a wide spectrum of illness. Nephrotic syndrome might also be associated with Cause of SRNS syndromic features with mutations in specific genes— Genetic causes eg, Denys-Drash syndrome and Frasier syndrome (WT1); The medical community has learnt much about the Pierson syndrome (LAMB2); nail-patella syndrome genetic causes for SRNS over the past decades. Mutations (LMX1B); Epstein syndrome, Sebastian syndrome, and in more than 70 genes encoding key podocyte proteins related illnesses (MYH9); MELAS syndrome and Leigh are recognised to cause the illness. Despite recognition syndrome (mitochondrial genes); Galloway-Mowat syn- of an increasing number of genetic causes, only drome (WDR73); and Schimke dysplasia (SMARCAL1), 30% of patients with sporadic SRNS show a defined as reviewed by Bierzynska and colleagues6 and Preston mutation.6 and colleagues.7 Genes associated with the occurrence of SRNS are broadly classified as involving: structural elements of the Circulating factor The probable cause for most patients with non-genetic 8,9 A SRNS is thought to be a circulating factor. Circum- stantial evidence exists that makes this theory quite probable, but it has been elusive to define the circulating factors responsible for SRNS.10 A large proportion of children with non-genetic SRNS relapse quickly after kidney transplantation: these patients often respond to plasma exchange or immune adsorption. Small animals infused with patient plasma, whole or its fractions, also develop proteinuria. In 1975, a vascular permeability factor was described.11 Other important suggestions of circulating factors include haemopexin, interleukin-13, cardiotrophin-like cytokine-1, and soluble urokinase-type plasminogen activator receptor.12–15 None of these sug- gested factors have been confirmed by independent research groups so far. B Kidney biopsy Renal histology is an important tool for diagnostic and prognostic categorisation. Biopsies should be examined by light, immunofluorescence, and electron microscopy to define their histological features. An ade quate biopsy should have approximately 25 glomeruli, especially when evaluating lesions that are focal or segmental. Biopsies with fewer glomeruli have low diagnostic accuracy. Common histological diagnoses include focal seg- mental glomerulosclerosis (FSGS) in 35–55% of patients, minimal change disease in 25–40% of patients, and idiopathic mesangioproliferative glomerulonephritis in 10–15% of patients (figure 1).16 In about 20% of patients, the histology shows membranous
Recommended publications
  • A Cytoskeleton Regulator AVIL Drives Tumorigenesis in Glioblastoma
    ARTICLE https://doi.org/10.1038/s41467-020-17279-1 OPEN A cytoskeleton regulator AVIL drives tumorigenesis in glioblastoma Zhongqiu Xie 1, Pawel Ł. Janczyk2,8, Ying Zhang3,8, Aiqun Liu4, Xinrui Shi1, Sandeep Singh 1, Loryn Facemire1, ✉ Kristopher Kubow5,ZiLi6, Yuemeng Jia1, Dorothy Schafer7, James W. Mandell1, Roger Abounader3 & Hui Li1,2 Glioblastoma is a deadly cancer, with no effective therapies. Better understanding and identification of selective targets are urgently needed. We found that advillin (AVIL) is 1234567890():,; overexpressed in all the glioblastomas we tested including glioblastoma stem/initiating cells, but hardly detectable in non-neoplastic astrocytes, neural stem cells or normal brain. Glioma patients with increased AVIL expression have a worse prognosis. Silencing AVIL nearly eradicated glioblastoma cells in culture, and dramatically inhibited in vivo xenografts in mice, but had no effect on normal control cells. Conversely, overexpressing AVIL promoted cell proliferation and migration, enabled fibroblasts to escape contact inhibition, and transformed immortalized astrocytes, supporting AVIL being a bona fide oncogene. We provide evidence that the tumorigenic effect of AVIL is partly mediated by FOXM1, which regulates LIN28B, whose expression also correlates with clinical prognosis. AVIL regulates the cytoskeleton through modulating F-actin, while mutants disrupting F-actin binding are defective in its tumorigenic capabilities. 1 Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA. 2 Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA. 3 Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA. 4 Tumor Hospital, Guangxi Medical University, Nanning 530021, China.
    [Show full text]
  • Circulating Supar in Two Cohorts of Primary FSGS
    CLINICAL RESEARCH www.jasn.org Circulating suPAR in Two Cohorts of Primary FSGS † ‡ Changli Wei,* Howard Trachtman, Jing Li,* Chuanhui Dong, Aaron L. Friedman,§ | | | Jennifer J. Gassman, June L. McMahan, Milena Radeva, Karsten M. Heil,¶ †† ‡‡ Agnes Trautmann,¶ Ali Anarat,** Sevinc Emre, Gian M. Ghiggeri, Fatih Ozaltin,§§ || ††† Dieter Haffner, Debbie S. Gipson,¶¶ Frederick Kaskel,*** Dagmar-Christiane Fischer, ‡‡‡ Franz Schaefer,¶ and Jochen Reiser, for the PodoNet and FSGS CT Study Consortia Departments of *Medicine and ‡Neurology, University of Miami Miller School of Medicine, Miami, Florida; †Department of Pediatrics, NYU Langone Medical Center, New York, New York; §Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; |Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio; ¶Center for Pediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany; **Department of Pediatric Nephrology, Cukurova University School of Medicine, Adana, Turkey; ††Department of Pediatrics, Istanbul Medical Faculty, University of Istanbul, Istanbul, Turkey; ‡‡Division of Nephrology, Dialysis, and Transplantation, Laboratory on Pathophysiology of Uremia, G. Gaslini Children’s Hospital, Genoa, Italy; §§Pediatric Nephrology Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey; ||Department of Pediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany; ¶¶Department of Pediatrics, University of Michigan, Ann Arbor, Michigan; ***Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York; †††Department of Pediatrics, Rostock University Hospital, Rostock, Germany; and ‡‡‡Department of Medicine, Rush University Medical Center, Chicago, Illinois ABSTRACT Overexpression of soluble urokinase receptor (suPAR) causes pathology in animal models similar to pri- mary FSGS, and one recent study demonstrated elevated levels of serum suPAR in patients with the disease.
    [Show full text]
  • Regulation of Calmodulin-Stimulated Cyclic Nucleotide Phosphodiesterase (PDE1): Review
    95-105 5/6/06 13:44 Page 95 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 18: 95-105, 2006 95 Regulation of calmodulin-stimulated cyclic nucleotide phosphodiesterase (PDE1): Review RAJENDRA K. SHARMA, SHANKAR B. DAS, ASHAKUMARY LAKSHMIKUTTYAMMA, PONNIAH SELVAKUMAR and ANURAAG SHRIVASTAV Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Cancer Research Division, Saskatchewan Cancer Agency, 20 Campus Drive, Saskatoon SK S7N 4H4, Canada Received January 16, 2006; Accepted March 13, 2006 Abstract. The response of living cells to change in cell 6. Differential inhibition of PDE1 isozymes and its environment depends on the action of second messenger therapeutic applications molecules. The two second messenger molecules cAMP and 7. Role of proteolysis in regulating PDE1A2 Ca2+ regulate a large number of eukaryotic cellular events. 8. Role of PDE1A1 in ischemic-reperfused heart Calmodulin-stimulated cyclic nucleotide phosphodiesterase 9. Conclusion (PDE1) is one of the key enzymes involved in the complex interaction between cAMP and Ca2+ second messenger systems. Some PDE1 isozymes have similar kinetic and 1. Introduction immunological properties but are differentially regulated by Ca2+ and calmodulin. Accumulating evidence suggests that the A variety of cellular activities are regulated through mech- activity of PDE1 is selectively regulated by cross-talk between anisms controlling the level of cyclic nucleotides. These Ca2+ and cAMP signalling pathways. These isozymes are mechanisms include synthesis, degradation, efflux and seque- also further distinguished by various pharmacological agents. stration of cyclic adenosine 3':5'-monophosphate (cAMP) and We have demonstrated a potentially novel regulation of PDE1 cyclic guanosine 3':5'- monophosphate (cGMP) within the by calpain.
    [Show full text]
  • Exome Sequencing Reveals Cubilin Mutation As a Single-Gene Cause of Proteinuria
    BRIEF COMMUNICATION www.jasn.org Exome Sequencing Reveals Cubilin Mutation as a Single-Gene Cause of Proteinuria Bugsu Ovunc,*† Edgar A. Otto,* Virginia Vega-Warner,* Pawaree Saisawat,* Shazia Ashraf,* Gokul Ramaswami,* Hanan M. Fathy,‡ Dominik Schoeb,* Gil Chernin,* Robert H. Lyons,§ ʈ Engin Yilmaz,† and Friedhelm Hildebrandt* ¶ ʈ Departments of *Pediatrics and Human Genetics, §Department of Biological Chemistry and DNA Sequencing Core, and ¶Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan; †Department of Medical Biology, Hacettepe University, Ankara, Turkey; and ‡The Pediatric Nephrology Unit, Alexandria University, Alexandria, Egypt ABSTRACT In two siblings of consanguineous parents with intermittent nephrotic-range pro- tion is still unknown.7 This forbids the use of teinuria, we identified a homozygous deleterious frameshift mutation in the gene cohort studies for gene identification and ne- CUBN, which encodes cubulin, using exome capture and massively parallel re- cessitates the ability to identify disease-caus- sequencing. The mutation segregated with affected members of this family and ing genes in single families. We therefore was absent from 92 healthy individuals, thereby identifying a recessive mutation in combined whole genome homozygosity CUBN as the single-gene cause of proteinuria in this sibship. Cubulin mutations mapping with consecutive whole human ex- cause a hereditary form of megaloblastic anemia secondary to vitamin B12 defi- ome capture (WHEC) and massively par- ciency, and proteinuria occurs in 50% of cases since cubilin is coreceptor for both allel re-sequencing to overcome this lim- 6 the intestinal vitamin B12-intrinsic factor complex and the tubular reabsorption of itation. In this way we here identify a protein in the proximal tubule.
    [Show full text]
  • 140503 IPF Signatures Supplement Withfigs Thorax
    Supplementary material for Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis Daryle J. DePianto1*, Sanjay Chandriani1⌘*, Alexander R. Abbas1, Guiquan Jia1, Elsa N. N’Diaye1, Patrick Caplazi1, Steven E. Kauder1, Sabyasachi Biswas1, Satyajit K. Karnik1#, Connie Ha1, Zora Modrusan1, Michael A. Matthay2, Jasleen Kukreja3, Harold R. Collard2, Jackson G. Egen1, Paul J. Wolters2§, and Joseph R. Arron1§ 1Genentech Research and Early Development, South San Francisco, CA 2Department of Medicine, University of California, San Francisco, CA 3Department of Surgery, University of California, San Francisco, CA ⌘Current address: Novartis Institutes for Biomedical Research, Emeryville, CA. #Current address: Gilead Sciences, Foster City, CA. *DJD and SC contributed equally to this manuscript §PJW and JRA co-directed this project Address correspondence to Paul J. Wolters, MD University of California, San Francisco Department of Medicine Box 0111 San Francisco, CA 94143-0111 [email protected] or Joseph R. Arron, MD, PhD Genentech, Inc. MS 231C 1 DNA Way South San Francisco, CA 94080 [email protected] 1 METHODS Human lung tissue samples Tissues were obtained at UCSF from clinical samples from IPF patients at the time of biopsy or lung transplantation. All patients were seen at UCSF and the diagnosis of IPF was established through multidisciplinary review of clinical, radiological, and pathological data according to criteria established by the consensus classification of the American Thoracic Society (ATS) and European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and the Latin American Thoracic Association (ALAT) (ref. 5 in main text). Non-diseased normal lung tissues were procured from lungs not used by the Northern California Transplant Donor Network.
    [Show full text]
  • Hypomethylation-Linked Activation of PLCE1 Impedes Autophagy and Promotes Tumorigenesis Through MDM2-Mediated Ubiquitination and Destabilization of P53
    Author Manuscript Published OnlineFirst on February 17, 2020; DOI: 10.1158/0008-5472.CAN-19-1912 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hypomethylation-linked activation of PLCE1 impedes autophagy and promotes tumorigenesis through MDM2-mediated ubiquitination and destabilization of p53 Yunzhao Chen1,3*, Huahua Xin1*, Hao Peng1*, Qi Shi1, Menglu Li1, Jie Yu3, Yanxia Tian1, Xueping Han1, Xi Chen1, Yi Zheng4, Jun Li5, Zhihao Yang1, Lan Yang1, Jianming Hu1, Xuan Huang2, Zheng Liu2, Xiaoxi Huang2, Hong Zhou6, Xiaobin Cui1**, Feng Li1,2** 1 Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi 832002, China; 2 Department of Pathology and Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China; 3 The people's hospital of Suzhou National Hi-Tech District, Suzhou 215010, China; 4 Department of Gastroenterology, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi 832002, China; 5 Department of Ultrasound, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi 832002, China; 6 Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, Australia. Running title: PLCE1 impedes autophagy via MDM2-p53 axis in ESCC *These authors contributed equally to this work. Corresponding authors: **Xiaobin Cui, Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi 832002, China. Phone: 86.0377.2850955; E-mail: [email protected]; **Feng Li, Department of Pathology and Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
    [Show full text]
  • Hypomethylation-Linked Activation of PLCE1 Impedes
    Published OnlineFirst February 17, 2020; DOI: 10.1158/0008-5472.CAN-19-1912 CANCER RESEARCH | MOLECULAR CELL BIOLOGY Hypomethylation-Linked Activation of PLCE1 Impedes Autophagy and Promotes Tumorigenesis through MDM2-Mediated Ubiquitination and Destabilization of p53 Yunzhao Chen1,2, Huahua Xin1, Hao Peng1, Qi Shi1, Menglu Li1,JieYu2, Yanxia Tian1, Xueping Han1, Xi Chen1, Yi Zheng3,JunLi4, Zhihao Yang1, Lan Yang1, Jianming Hu1, Xuan Huang5, Zheng Liu5, Xiaoxi Huang5, Hong Zhou6, Xiaobin Cui1, and Feng Li1,5 ABSTRACT ◥ Esophageal squamous cell carcinoma (ESCC) is one of the dead- Significance: These findings identify hypomethylation- liest malignant diseases. Multiple studies with large clinic-based mediated activation of PLCE1 as a potential oncogene that cohorts have revealed that variations of phospholipase C epsilon 1 blocks cellular autophagy of esophageal carcinoma by facilitat- (PLCE1) correlate with esophageal cancer susceptibility. However, ing the MDM2-dependent ubiquitination of p53 and subsequent the causative role of PLCE1 in ESCC has remained elusive. Here, we degradation. observed that hypomethylation-mediated upregulation of PLCE1 Graphical Abstract: http://cancerres.aacrjournals.org/content/ expression was implicated in esophageal carcinogenesis and poor canres/80/11/2175/F1.large.jpg. prognosis in ESCC cohorts. PLCE1 inhibited cell autophagy and suppressed the protein expression of p53 and various p53-targeted genes in ESCC. Moreover, PLCE1 decreased the half-life of p53 and Normal cells Cancer cells promoted p53 ubiquitination, whereas it increased the half-life of PLCE1 Cytoplasm Cytoplasm mouse double minute 2 homolog (MDM2) and inhibited its ubiqui- wtp53 wtp53 tination, leading to MDM2 stabilization. Mechanistically, the func- MDM2 MDM2 wtp53 MDM2 MDM2 Nucleus tion of PLCE1 correlated with its direct binding to both p53 and Nucleus wtp53 Ub Ub MDM2, which promoted MDM2-dependent ubiquitination of p53 PLCE1 MDM2 wtp53 Ub wtp53 wtp53 and subsequent degradation in vitro.
    [Show full text]
  • Kinase-Inactive ZAP-70 Thymocyte Development By
    An Improved Retroviral Gene Transfer Technique Demonstrates Inhibition of CD4− CD8− Thymocyte Development by Kinase-Inactive ZAP-70 This information is current as of September 23, 2021. Takehiko Sugawara, Vincenzo Di Bartolo, Tadaaki Miyazaki, Hiromitsu Nakauchi, Oreste Acuto and Yousuke Takahama J Immunol 1998; 161:2888-2894; ; http://www.jimmunol.org/content/161/6/2888 Downloaded from References This article cites 49 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/161/6/2888.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 23, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. An Improved Retroviral Gene Transfer Technique Demonstrates Inhibition of CD42CD82 Thymocyte Development by Kinase-Inactive ZAP-701 Takehiko Sugawara,* Vincenzo Di Bartolo,§ Tadaaki Miyazaki,‡ Hiromitsu Nakauchi,* Oreste Acuto,§ and Yousuke Takahama2*† ZAP-70 is a Syk family tyrosine kinase that plays an essential role in initiating TCR signals.
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • Podocin Inactivation in Mature Kidneys Causes Focal Segmental Glomerulosclerosis and Nephrotic Syndrome
    BASIC RESEARCH www.jasn.org Podocin Inactivation in Mature Kidneys Causes Focal Segmental Glomerulosclerosis and Nephrotic Syndrome Ge´raldine Mollet,*† Julien Ratelade,*† Olivia Boyer,*†‡ Andrea Onetti Muda,*§ ʈ Ludivine Morisset,*† Tiphaine Aguirre Lavin,*† David Kitzis,*† Margaret J. Dallman, ʈ Laurence Bugeon, Norbert Hubner,¶ Marie-Claire Gubler,*† Corinne Antignac,*†** and Ernie L. Esquivel*† *INSERM, U574, Hoˆpital Necker-Enfants Malades, Paris, France; †Faculte´deMe´ decine Rene´ Descartes, Universite´ Paris Descartes, Paris, France; ‡Pediatric Nephrology Department and **Department of Genetics, Hoˆpital Necker- Enfants Malades, Assistance Publique-Hoˆpitaux de Paris, Paris, France; §Department of Pathology, Campus ʈ Biomedico University, Rome, Italy; Department of Biological Sciences, Imperial College London, London, England; and ¶Max-Delbruck Center for Molecular Medicine, Berlin, Germany ABSTRACT Podocin is a critical component of the glomerular slit diaphragm, and genetic mutations lead to both familial and sporadic forms of steroid-resistant nephrotic syndrome. In mice, constitutive absence of podocin leads to rapidly progressive renal disease characterized by mesangiolysis and/or mesangial sclerosis and nephrotic syndrome. Using established Cre-loxP technology, we inactivated podocin in the adult mouse kidney in a podocyte-specific manner. Progressive loss of podocin in the glomerulus recapitu- lated albuminuria, hypercholesterolemia, hypertension, and renal failure seen in nephrotic syndrome in humans. Lesions of FSGS appeared
    [Show full text]
  • HHS Public Access Author Manuscript
    HHS Public Access Author manuscript Author Manuscript Author ManuscriptJAMA Psychiatry Author Manuscript. Author Author Manuscript manuscript; available in PMC 2015 August 03. Published in final edited form as: JAMA Psychiatry. 2014 June ; 71(6): 657–664. doi:10.1001/jamapsychiatry.2014.176. Identification of Pathways for Bipolar Disorder A Meta-analysis John I. Nurnberger Jr, MD, PhD, Daniel L. Koller, PhD, Jeesun Jung, PhD, Howard J. Edenberg, PhD, Tatiana Foroud, PhD, Ilaria Guella, PhD, Marquis P. Vawter, PhD, and John R. Kelsoe, MD for the Psychiatric Genomics Consortium Bipolar Group Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis (Nurnberger, Koller, Edenberg, Foroud); Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis (Nurnberger, Foroud); Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism Intramural Research Program, Bethesda, Maryland (Jung); Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis (Edenberg); Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine (Guella, Vawter); Department of Psychiatry, School of Medicine, Corresponding Author: John I. Nurnberger Jr, MD, PhD, Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, 791 Union Dr, Indianapolis, IN 46202 ([email protected]). Author Contributions: Drs Koller and Vawter had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Nurnberger, Koller, Edenberg, Vawter. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Nurnberger, Koller, Jung, Vawter.
    [Show full text]
  • A-Kinase Anchoring Protein–Calcineurin Signaling in Long-Term Depression of Gabaergic Synapses
    2650 • The Journal of Neuroscience, February 6, 2013 • 33(6):2650–2660 Cellular/Molecular A-Kinase Anchoring Protein–Calcineurin Signaling in Long-Term Depression of GABAergic Synapses Matthieu Dacher, Shawn Gouty, Steven Dash, Brian M. Cox, and Fereshteh S. Nugent Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814 The postsynaptic scaffolding A-kinase anchoring protein 79/150 (AKAP79/150) signaling complex regulates excitatory synaptic trans- mission and strength through tethering protein kinase A (PKA), PKC, and calcineurin (CaN) to the postsynaptic densities of neurons (Sanderson and Dell’Acqua, 2011), but its role in inhibitory synaptic transmission and plasticity is unknown. Using immunofluorescence and whole-cell patch-clamp recording in rat midbrain slices, we show that activation of postsynaptic D2-like family of dopamine (DA) receptor in the ventral tegmental area (VTA) induces long-term depression (LTD) of GABAergic synapses on DA neurons through an inositol triphosphate receptor-mediated local rise in postsynaptic Ca 2ϩ and CaN activation accompanied by PKA inhibition, which requires AKAP150 as a bridging signaling molecule. Our data also illuminate a requirement for a clathrin-mediated internalization of GABAA receptors in expression of LTDGABA. Moreover, disruption of AKAP–PKA anchoring does not affect glutamatergic synapses onto DA neurons, suggesting that the PKA–AKAP–CaN complex is uniquely situated at GABAA receptor synapses in VTA DA neurons to regulate plasticity associated with GABAA receptors. Drug-induced modulation of GABAergic plasticity in the VTA through such novel signaling mechanisms has the potential to persistently alter the output of individual DA neurons and of the VTA, which may contribute to the reinforcing or addictive properties of drugs of abuse.
    [Show full text]