Induction of B7-1 in podocytes is associated with nephrotic syndrome

Abstract

Kidney podocytes and their slit diaphragms form the final barrier to urinary protein loss. This explains why podocyte injury is typically associated with nephrotic syndrome. The present study uncovered an unanticipated novel role for costimulatory molecule B7-1 in podocytes as an inducible modifier of glomerular permselectivity. B7-1 in podocytes was found in genetic, drug-induced, immune-mediated, and bacterial toxin-induced experimental kidney diseases with nephrotic syndrome. The clinical significance of our results is underscored by the observation that podocyte expression of B7-1 correlated with the severity of human lupus nephritis. In vivo, exposure to low-dose LPS rapidly upregulates B7-1 in podocytes of WT and SCID mice, leading to nephrotic-range proteinuria. Mice lacking B7-1 are protected from LPS-induced nephrotic syndrome, suggesting a link between podocyte B7-1 expression and proteinuria. LPS signaling through toll-like receptor-4 reorganized the podocyte actin cytoskeleton in vitro, and activation of B7-1 in cultured podocytes led to reorganization of vital slit diaphragm proteins. In summary, upregulation of B7-1 in podocytes may contribute to the pathogenesis of proteinuria by disrupting the glomerular filter and provides a novel molecular target to tackle proteinuric kidney diseases. Our findings suggest a novel function for B7-1 in danger signaling by nonimmune cells. 1390The Nonstandard abbreviations used: foot process (FP); glomerular basement membrane (GBM); puromycin aminonucleoside (PAN); slit diaphragm (SD); toll-like receptor (TLR).

Up-Regulation of CD74 Expression in Parietal Epithelial Cells in a Mouse Model of Focal Segmental Glomerulosclerosis

“…As reported previously, LPS administration (15 μg/g) to Balb/c mice is known to induce significant proteinuria associated with reversible podocyte injury [21]. To decrease lethality, we reduced the dose of LPS to 7.5 μg/g, and LPS was intraperitoneally administered to the mice 3 weeks after ADR injection (LPS-treated ADR mice; fig.…”

“…These findings indicate that the CD74-positive enlarged cells observed rapidly after LPS treatment reflected the amplification of PEC activation, which was already underway after ADR injection. Because LPS treatment is known to induce massive proteinuria via podocyte stimulation [21,32], we believe that PECs respond to podocyte injury with LPS treatment in ADR mice through morphological and phenotypic changes [33]. In addition to indirect effects through massive proteinuria with podocyte injury, a direct effect of LPS in PECs injury, which gradually progressed in ADR mice during the course of the treatment, should also be considered.…”

“…Briefly, the mouse model of LPS-induced proteinuria [21] was established by IP injections of low-dose (7.5 µg/g/BW) or high-dose (15 µg/g/BW) LPS. Protein-overload nephropathy was induced in mice [22,23] by IP injection for 8 days of BSA (Sigma A-9430; Sigma) dissolved in saline (200 mg/ml), beginning with 2 mg/g/BW and increasing the daily dose by 2 mg/g/BW until reaching a final concentration of 10 mg/g/BW.…”

Serum Interleukin 13 Level in Steroid Sensitive Nephrotic Syndrome

“…Thus, IL13 may injure glomerular visceral cells and increase glomerular permeability (4). Moreover, recent studies have shown that IL-13 induces the expression of CD80 by podocytes, resulting in proteinuria and epithelial cell foot process effacement (6,7).…”

Back to the Future: Therapies for Idiopathic Nephrotic Syndrome

“…B7-1 is not expressed by normal podocytes but has been found in human podocytes with various glomerulonephritidies including FSGS and MPGN. Increased podocyte expression of B7-1 has additionally been found in mouse models of proteinuria [32]. Yu et al reported that B7-1 influences podocyte structure and function.…”