{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:46:36Z","timestamp":1790725596681,"version":"4.1.0"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","funder":[{"DOI":"10.13039\/100007451","name":"Cell Science Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007451","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shinya Foundation"},{"DOI":"10.13039\/100008732","name":"Uehara Memorial Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008732","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-399126"],"award-info":[{"award-number":["PJT-399126"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000191","name":"Kidney Foundation of Canada","doi-asserted-by":"publisher","award":["BRG-180016"],"award-info":[{"award-number":["BRG-180016"]}],"id":[{"id":"10.13039\/501100000191","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>\n                      Dysregulation of Cdc42 and other members of the Rho family of small GTPases in podocytes contributes to the pathogenesis of proteinuria. However, the upstream regulatory mechanisms for Cdc42 activity in podocytes are largely unknown. The authors identified ARHGEF7 (commonly known as\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -PIX) as a predominant guanine nucleotide exchange factor and activator of Cdc42 in podocytes. They also demonstrated that\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -PIX is required for the maintenance of podocyte architecture and glomerular function\n                      <jats:italic toggle=\"yes\">via<\/jats:italic>\n                      Cdc42 and its downstream effects on Yes-associated protein (YAP) activity. Elucidating the precise details of how numerous regulatory proteins maintain the delicate balance of Rho GTPases in podocytes will be essential in understanding the pathogenesis of proteinuric glomerular diseases and identifying therapeutic targets.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -PIX) knockout mice by crossing\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -PIX floxed mice with Podocin-Cre mice. Using shRNA, we established cultured mouse podocytes with\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -PIX knockdown and their controls.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -PIX as a predominant guanine nucleotide exchange factor that interacts with Cdc42 in human podocytes. Podocyte-specific\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -PIX knockout mice developed progressive proteinuria and kidney failure with global or segmental glomerulosclerosis in adulthood. Glomerular podocyte density gradually decreased in podocyte-specific\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -PIX knockout mice, indicating podocyte loss. Compared with controls, glomeruli from podocyte-specific\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -PIX knockout mice and cultured mouse podocytes with\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -PIX knockdown exhibited significant reduction in Cdc42 activity. Loss of\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -PIX promoted podocyte apoptosis, which was mediated by the reduced activity of the prosurvival transcriptional regulator Yes-associated protein.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings indicate that\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -PIX is required for the maintenance of podocyte architecture and glomerular function\n                      <jats:italic toggle=\"yes\">via<\/jats:italic>\n                      Cdc42 and its downstream Yes-associated protein activities. This appears to be the first evidence that a Rho\u2013guanine nucleotide exchange factor plays a critical role in podocytes.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2019090982","type":"journal-article","created":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T18:25:32Z","timestamp":1584555932000},"page":"996-1008","source":"Crossref","is-referenced-by-count":21,"title":["ARHGEF7 (\u03b2-PIX) Is Required for the Maintenance of Podocyte Architecture and Glomerular 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