| First Author | Matsuda J | Year | 2020 |
| Journal | J Am Soc Nephrol | Volume | 31 |
| Issue | 5 | Pages | 996-1008 |
| PubMed ID | 32188698 | Mgi Jnum | J:319398 |
| Mgi Id | MGI:6863773 | Doi | 10.1681/ASN.2019090982 |
| Citation | Matsuda J, et al. (2020) ARHGEF7 (beta-PIX) Is Required for the Maintenance of Podocyte Architecture and Glomerular Function. J Am Soc Nephrol 31(5):996-1008 |
| abstractText | BACKGROUND: Previous studies showed that Cdc42, a member of the prototypical Rho family of small GTPases and a regulator of the actin cytoskeleton, is critical for the normal development and health of podocytes. However, upstream regulatory mechanisms for Cdc42 activity in podocytes are largely unknown. METHODS: We used a proximity-based ligation assay, BioID, to identify guanine nucleotide exchange factors that activate Cdc42 in immortalized human podocytes. We generated podocyte-specific ARHGEF7 (commonly known as beta-PIX) knockout mice by crossing beta-PIX floxed mice with Podocin-Cre mice. Using shRNA, we established cultured mouse podocytes with beta-PIX knockdown and their controls. RESULTS: We identified beta-PIX as a predominant guanine nucleotide exchange factor that interacts with Cdc42 in human podocytes. Podocyte-specific beta-PIX knockout mice developed progressive proteinuria and kidney failure with global or segmental glomerulosclerosis in adulthood. Glomerular podocyte density gradually decreased in podocyte-specific beta-PIX knockout mice, indicating podocyte loss. Compared with controls, glomeruli from podocyte-specific beta-PIX knockout mice and cultured mouse podocytes with beta-PIX knockdown exhibited significant reduction in Cdc42 activity. Loss of beta-PIX promoted podocyte apoptosis, which was mediated by the reduced activity of the prosurvival transcriptional regulator Yes-associated protein. CONCLUSIONS: These findings indicate that beta-PIX is required for the maintenance of podocyte architecture and glomerular function via Cdc42 and its downstream Yes-associated protein activities. This appears to be the first evidence that a Rho-guanine nucleotide exchange factor plays a critical role in podocytes. |
