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. 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 × 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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For confirmation of the difference in the infectivity of hepatitis B surface antigen (HBS Ag)-positive serum according to differences in the e antigen system, four chimpanzees were inoculated with serum positive for hepatitis B e antigen (HBe Ag), and three chimpanzees were inoculated with serum positive for antibody to HBe Ag (anti-HBe). Since the infectivity titrations are not yet completed, the end infectivity titer of each serum is not known. All four chimpanzees given injections of 10(-1), 10(-4), or 10(-8) dilutions of HBe Ag-positive serum developed hepatitis B virus infection, whereas the one chimpanzee injected with undiluted anti-HBe-positive serum became infected, and other chimpanzees injected with diluted anti-HBe-positive sera did not. As judged from the length of the incubation period before appearance of HBS Ag in blood, there seemed to be a remarkable difference in infectivity between the HBe Ag-positive serum and the anti-HBe-positive serum; the former serum was 10(8) times more infectious than the latter.