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Ebarasi, Lwaki
Publications (4 of 4) Show all publications
Falkevall, A., Mehlem, A., Palombo, I., Sahlgren, B. H., Ebarasi, L., He, L., . . . Eriksson, U. (2017). Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease. Cell Metabolism, 25(3), 713-726
Open this publication in new window or tab >>Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease
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2017 (English)In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 25, no 3, p. 713-726Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-318926 (URN)10.1016/j.cmet.2017.01.004 (DOI)000396355700026 ()28190774 (PubMedID)
Funder
Swedish Heart Lung Foundation, 20110451, 20120077Swedish Research Council, 2011-03861Swedish Cancer Society, CAN 2011/792, CAN 2014/630
Available from: 2017-04-05 Created: 2017-04-05 Last updated: 2017-11-29Bibliographically approved
Ebarasi, L., Ashraf, S., Bierzynska, A., Gee, H. Y., McCarthy, H. J., Lovric, S., . . . Majumdar, A. (2015). Defects of CRB2 Cause Steroid-Resistant Nephrotic Syndrome. American Journal of Human Genetics, 96(1), 153-161
Open this publication in new window or tab >>Defects of CRB2 Cause Steroid-Resistant Nephrotic Syndrome
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2015 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 96, no 1, p. 153-161Article in journal (Refereed) Published
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.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-247168 (URN)10.1016/j.ajhg.2014.11.014 (DOI)000347707800012 ()25557779 (PubMedID)
Available from: 2015-03-16 Created: 2015-03-13 Last updated: 2018-01-11Bibliographically approved
Kok, F. O., Shin, M., Ni, C.-W., Gupta, A., Grosse, A. S., van Impel, A., . . . Lawson, N. D. (2015). Reverse Genetic Screening Reveals Poor Correlation between Morpholino-Induced and Mutant Phenotypes in Zebrafish. Developmental Cell, 32(1), 97-108
Open this publication in new window or tab >>Reverse Genetic Screening Reveals Poor Correlation between Morpholino-Induced and Mutant Phenotypes in Zebrafish
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2015 (English)In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 32, no 1, p. 97-108Article in journal (Refereed) Published
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.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-245368 (URN)10.1016/j.devcel.2014.11.018 (DOI)000347907200012 ()25533206 (PubMedID)
Available from: 2015-02-26 Created: 2015-02-26 Last updated: 2017-12-04Bibliographically approved
He, B., Ebarasi, L., Zhao, Z., Guo, J., Ojala, J. R. M., Hultenby, K., . . . Tryggvason, K. (2014). Lmx1b and FoxC Combinatorially Regulate Podocin Expression in Podocytes. Journal of the American Society of Nephrology, 25(12), 2764-2777
Open this publication in new window or tab >>Lmx1b and FoxC Combinatorially Regulate Podocin Expression in Podocytes
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2014 (English)In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 25, no 12, p. 2764-2777Article in journal (Refereed) Published
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.

National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-240216 (URN)10.1681/ASN.2012080823 (DOI)000345607500012 ()24854274 (PubMedID)
Available from: 2015-01-07 Created: 2015-01-06 Last updated: 2017-12-05Bibliographically approved
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