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  • 1.
    Ebarasi, Lwaki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ashraf, Shazia
    Bierzynska, Agnieszka
    Gee, Heon Yung
    McCarthy, Hugh J.
    Lovric, Svjetlana
    Sadowski, Carolin E.
    Pabst, Werner
    Vega-Warner, Virginia
    Fang, Humphrey
    Koziell, Ania
    Simpson, Michael A.
    Dursun, Ismail
    Serdaroglu, Erkin
    Levy, Shawn
    Saleem, Moin A.
    Hildebrandt, Friedhelm
    Majumdar, Arindam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Defects of CRB2 Cause Steroid-Resistant Nephrotic Syndrome2015In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 96, no 1, p. 153-161Article in journal (Refereed)
    Abstract [en]

    Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.

  • 2.
    Falkevall, Annelie
    et al.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Mehlem, Annika
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Palombo, Isolde
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Sahlgren, Benjamin Heller
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Ebarasi, Lwaki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden.; Karolinska Inst, Dept Clin Sci Intervent & Technol, Div Renal Med, S-14186 Stockholm, Sweden.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ytterberg, A. Jimmy
    Karolinska Inst, Div Physiol Chem 1, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden.;Karolinska Inst, Rheumatol Unit, Dept Med, S-17176 Stockholm, Sweden..
    Olauson, Hannes
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Div Renal Med, S-14186 Stockholm, Sweden..
    Axelsson, Jonas
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Apheresis & Stem Cell Handling, S-14186 Stockholm, Sweden..
    Sundelin, Birgitta
    Karolinska Inst, Dept Oncol Pathol, S-17176 Stockholm, Sweden.;Karolinska Univ Hosp, S-17176 Stockholm, Sweden..
    Patrakka, Jaakko
    Karolinska Inst, Karolinska Univ Hosp, Dept Lab Med, KI AZ Integrated CardioMetabol Ctr ICMC, S-14157 Huddinge, Sweden..
    Scotney, Pierre
    CSL Ltd, Parkville, Vic 3052, Australia..
    Nash, Andrew
    CSL Ltd, Parkville, Vic 3052, Australia..
    Eriksson, Ulf
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease2017In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 25, no 3, p. 713-726Article in journal (Refereed)
    Abstract [en]

    Diabetic kidney disease (DKD) is the most common cause of severe renal disease, and few treatment options are available today that prevent the progressive loss of renal function. DKD is characterized by altered glomerular filtration and proteinuria. A common observation in DKD is the presence of renal steatosis, but the mechanism(s) underlying this observation and to what extent they contribute to disease progression are unknown. Vascular endothelial growth factor B (VEGF-B) controls muscle lipid accumulation through regulation of endothelial fatty acid transport. Here, we demonstrate in experimental mouse models of DKD that renal VEGF-B expression correlates with the severity of disease. Inhibiting VEGF-B signaling in DKD mouse models reduces renal lipotoxicity, re-sensitizes podocytes to insulin signaling, inhibits the development of DKD-associated pathologies, and prevents renal dysfunction. Further, we show that elevated VEGF-B levels are found in patients with DKD, suggesting that VEGF-B antagonism represents a novel approach to treat DKD.

  • 3. He, Bing
    et al.
    Ebarasi, Lwaki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Zhao, Zhe
    Guo, Jing
    Ojala, Juha R. M.
    Hultenby, Kjell
    De Val, Sarah
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Tryggvason, Karl
    Lmx1b and FoxC Combinatorially Regulate Podocin Expression in Podocytes2014In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 25, no 12, p. 2764-2777Article in journal (Refereed)
    Abstract [en]

    Podocin is a key protein of the kidney podocyte slit diaphragm protein complex, an important part of the glomerular filtration barrier. Mutations in the human podocin gene NPHS2 cause familial or sporadic forms of renal disease owing to the disruption of filtration barrier integrity. The exclusive expression of NPHS2 in podocytes reflects its unique function and raises interesting questions about its transcriptional regulation. Here, we further define a 2.5-kb zebrafish nphs2 promoter fragment previously described and identify a 49-bp podocyte-specific transcriptional enhancer using Tol2-mediated G(0) transgenesis in zebrafish. Within this enhancer, we identified a cis-acting element composed of two adjacent DNA-binding sites (FLAT-E and forkhead) bound by transcription factors Lnnx1b and FoxC. In zebrafish, double knockdown of Lmx1b and FoxC orthologs using morpholino doses that caused no or minimal phenotypic changes upon individual knockdown completely disrupted podocyte development in 40% of injected embryos. Co-overexpression of the two genes potently induced endogenous nphs2 expression in zebrafish podocytes. We found that the NPHS2 promoter also contains a cis-acting Lmx1b-FoxC motif that binds LMX1B and FoxC2. Furthermore, a genome-wide search identified several genes that carry the Lmx1b-FoxC motif in their promoter regions. Among these candidates, motif-driven podocyte enhancer activity of CCNC and MEIS2 was functionally analyzed in vivo. Our results show that podocyte expression of some genes is combinatorially regulated by two transcription factors interacting synergistically with a common enhancer. This finding provides insights into transcriptional mechanisms required for normal and pathologic podocyte functions.

  • 4. Kok, Fatma O.
    et al.
    Shin, Masahiro
    Ni, Chih-Wen
    Gupta, Ankit
    Grosse, Ann S.
    van Impel, Andreas
    Kirchmaier, Bettina C.
    Peterson-Maduro, Josi
    Kourkoulis, George
    Male, Ira
    DeSantis, Dana F.
    Sheppard-Tindell, Sarah
    Ebarasi, Lwaki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Schulte-Merker, Stefan
    Wolfe, Scot A.
    Lawson, Nathan D.
    Reverse Genetic Screening Reveals Poor Correlation between Morpholino-Induced and Mutant Phenotypes in Zebrafish2015In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 32, no 1, p. 97-108Article in journal (Refereed)
    Abstract [en]

    The widespread availability of programmable site-specific nucleases now enables targeted gene disruption in the zebrafish. In this study, we applied site-specific nucleases to generate zebrafish lines bearing individual mutations in more than 20 genes. We found that mutations in only a small proportion of genes caused defects in embryogenesis. Moreover, mutants for ten different genes failed to recapitulate published Morpholino-induced phenotypes (morphants). The absence of phenotypes in mutant embryos was not likely due to maternal effects or failure to eliminate gene function. Consistently, a comparison of published morphant defects with the Sanger Zebrafish Mutation Project revealed that approximately 80% of morphant phenotypes were not observed in mutant embryos, similar to our mutant collection. Based on these results, we suggest that mutant phenotypes become the standard metric to define gene function in zebrafish, after which Morpholinos that recapitulate respective phenotypes could be reliably applied for ancillary analyses.

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