Journal
NATURE GENETICS
Volume 43, Issue 5, Pages 459-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.792
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Funding
- Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan [3023168]
- MEXT, Japan [17020003]
- Grants-in-Aid for Scientific Research [17020003] Funding Source: KAKEN
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Severe proteinuria is a defining factor of nephrotic syndrome irrespective of the etiology. Investigation of congenital nephrotic syndrome has shown that dysfunction of glomerular epithelial cells (podocytes) plays a crucial role in this disease(1). Acquired nephrotic syndrome is also assumed to be associated with podocyte injury. Here we identify an association between variants in GPC5, encoding glypican-5, and acquired nephrotic syndrome through a genome-wide association study and replication analysis (P value under a recessive model (P-rec) = 6.0 x 10(-11), odds ratio = 2.54). We show that GPC5 is expressed in podocytes and that the risk genotype is associated with higher expression. We further show that podocyte-specific knockdown and systemic short interfering RNA injection confers resistance to podocyte injury in mouse models of nephrosis. This study identifies GPC5 as a new susceptibility gene for nephrotic syndrome and implicates GPC5 as a promising therapeutic target for reducing podocyte vulnerability in glomerular disease.
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