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      An inducible mouse model of podocin-mutation-related nephrotic syndrome

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          Abstract

          Mutations in the NPHS2 gene, encoding podocin, cause hereditary nephrotic syndrome. The most common podocin mutation, R138Q, is associated with early disease onset and rapid progression to end-stage renal disease. Knock-in mice carrying a R140Q mutation, the mouse analogue of human R138Q, show developmental arrest of podocytes and lethal renal failure at neonatal age. Here we created a conditional podocin knock-in model named NPHS2 R140Q/- , using a tamoxifen-inducible Cre recombinase, which permits to study the effects of the mutation in postnatal life. Within the first week of R140Q hemizygosity induction the animals developed proteinuria, which peaked after 4–5 weeks. Subsequently the animals developed progressive renal failure, with a median survival time of 12 (95% CI: 11–13) weeks. Foot process fusion was observed within one week, progressing to severe and global effacement in the course of the disease. The number of podocytes per glomerulus gradually diminished to 18% compared to healthy controls 12–16 weeks after induction. The fraction of segmentally sclerosed glomeruli was 25%, 85% and 97% at 2, 4 and 8 weeks, respectively. Severe tubulointerstitial fibrosis was present at later disease stage and was correlated quantitatively with the level of proteinuria at early disease stages. While R140Q podocin mRNA expression was elevated, protein abundance was reduced by more than 50% within one week following induction. Whereas miRNA21 expression persistently increased during the first 4 weeks, miRNA-193a expression peaked 2 weeks after induction. In conclusion, the inducible R140Q-podocin mouse model is an auspicious model of the most common genetic cause of human nephrotic syndrome, with a spontaneous disease course strongly reminiscent of the human disorder. This model constitutes a valuable tool to test the efficacy of novel pharmacological interventions aimed to improve podocyte function and viability and attenuate proteinuria, glomerulosclerosis and progressive renal failure.

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          Most cited references45

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          NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome.

          Familial idiopathic nephrotic syndromes represent a heterogeneous group of kidney disorders, and include autosomal recessive steroid-resistant nephrotic syndrome, which is characterized by early childhood onset of proteinuria, rapid progression to end-stage renal disease and focal segmental glomerulosclerosis. A causative gene for this disease, NPHS2, was mapped to 1q25-31 and we report here its identification by positional cloning. NPHS2 is almost exclusively expressed in the podocytes of fetal and mature kidney glomeruli, and encodes a new integral membrane protein, podocin, belonging to the stomatin protein family. We found ten different NPHS2 mutations, comprising nonsense, frameshift and missense mutations, to segregate with the disease, demonstrating a crucial role for podocin in the function of the glomerular filtration barrier.
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            Congenital nephrotic syndrome in mice lacking CD2-associated protein.

            CD2-associated protein (CD2AP) is an 80-kilodalton protein that is critical for stabilizing contacts between T cells and antigen-presenting cells. In CD2AP-deficient mice, immune function was compromised, but the mice died at 6 to 7 weeks of age from renal failure. In the kidney, CD2AP was expressed primarily in glomerular epithelial cells. Knockout mice exhibited defects in epithelial cell foot processes, accompanied by mesangial cell hyperplasia and extracellular matrix deposition. Supporting a role for CD2AP in the specialized cell junction known as the slit diaphragm, CD2AP associated with nephrin, the primary component of the slit diaphragm.
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              Smad3-mediated upregulation of miR-21 promotes renal fibrosis.

              TGF-β/Smad signaling plays a role in fibrogenesis, but therapies targeting TGF-β are ineffective in treating renal fibrosis. Here, we explored the therapeutic potential of targeting TGF-β-induced microRNA in the progression of renal fibrosis. Microarray analysis and real-time PCR revealed upregulation of miR-21 in tubular epithelial cells (TECs) in response to TGF-β. Lack of Smad3, but not lack of Smad2, prevented cells from upregulating miR-21 in response to TGF-β. In addition, Smad3-deficient mice were protected from upregulation of miR-21 and fibrosis in the unilateral ureteral obstruction model. In contrast, conditional knockout of Smad2 enhanced miR-21 expression and renal fibrosis. Furthermore, ultrasound-microbubble-mediated gene transfer of a miR-21-knockdown plasmid halted the progression of renal fibrosis in established obstructive nephropathy. In conclusion, these data demonstrate that Smad3, but not Smad2, signaling increases expression of miR-21, which promotes renal fibrosis. Inhibition of miR-21 may be a therapeutic approach to suppress renal fibrosis.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Visualization
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Visualization
                Role: Formal analysisRole: MethodologyRole: Validation
                Role: ConceptualizationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: Writing – review & editing
                Role: Visualization
                Role: MethodologyRole: Visualization
                Role: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                19 October 2017
                2017
                : 12
                : 10
                : e0186574
                Affiliations
                [1 ] Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany
                [2 ] INSERM, U1163, Imagine Institute, Laboratory of Hereditary Kidney Diseases, Paris, France
                [3 ] Paris Descartes-Sorbonne Paris Cité University, Paris, France
                [4 ] Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, Philipps-University Marburg, Marburg, Germany
                [5 ] Institute for Pathology, University of Heidelberg, Heidelberg, Germany
                [6 ] Institute for Anatomy and Cell Biology, University of Heidelberg, Heidelberg, Germany
                [7 ] Wellcome Trust Centre for Cell Matrix Research, University of Manchester, Manchester, United Kingdom
                [8 ] Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom
                [9 ] Department of Genetics, Necker Hospital, Assistance Publique—Hôpitaux de Paris, Paris, France
                University of Houston, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-0678-7900
                Article
                PONE-D-17-25408
                10.1371/journal.pone.0186574
                5648285
                29049388
                5cd098d6-5950-4f1a-b8e2-69ffc14336c2
                © 2017 Tabatabaeifar et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 12 July 2017
                : 10 September 2017
                Page count
                Figures: 9, Tables: 1, Pages: 21
                Funding
                This work has been made possible by support received from the EU 7th Framework Programme (EURenOmics, grant 2012-305608) and State funding from the Agence Nationale de la Recherche under "Investissements d'avenir" program (ANR-10-IAHU-01).
                Categories
                Research Article
                Research and Analysis Methods
                Experimental Organism Systems
                Model Organisms
                Mouse Models
                Research and Analysis Methods
                Model Organisms
                Mouse Models
                Research and Analysis Methods
                Experimental Organism Systems
                Animal Models
                Mouse Models
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Glomeruli
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Glomeruli
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Proteinuria
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Proteinuria
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Nephrology
                Renal Failure
                Biology and Life Sciences
                Developmental Biology
                Fibrosis
                Research and Analysis Methods
                Animal Studies
                Animal Models of Disease
                Biology and Life Sciences
                Genetics
                Phenotypes
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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