{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T07:49:17Z","timestamp":1768636157438,"version":"3.49.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,6,10]],"date-time":"2020-06-10T00:00:00Z","timestamp":1591747200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,6,10]],"date-time":"2020-06-10T00:00:00Z","timestamp":1591747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Dominant and recessive mutations in podocalyxin (<jats:italic>PODXL<\/jats:italic>) are associated with human kidney disease. Interestingly, some <jats:italic>PODXL<\/jats:italic> mutations manifest as anuria while others are associated with proteinuric kidney disease. <jats:italic>PODXL<\/jats:italic> heterozygosity is associated with adult-onset kidney disease and podocalyxin shedding into the urine is a common biomarker of a variety nephrotic syndromes. It is unknown, however, how various lesions in <jats:italic>PODXL<\/jats:italic> contribute to these disparate disease pathologies. Here we generated two mouse stains: one that deletes <jats:italic>Podxl<\/jats:italic> in developmentally mature podocytes (<jats:italic>Podxl<\/jats:italic><jats:sup>\u2206Pod<\/jats:sup>) and a second that is heterozygous for podocalyxin in all tissues (<jats:italic>Podxl<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup>). We used histologic and ultrastructural analyses, as well as clinical chemistry assays to evaluate kidney development and function in these strains. In contrast to null knockout mice (<jats:italic>Podxl<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>), which die shortly after birth from anuria and hypertension, <jats:italic>Podxl<\/jats:italic><jats:sup>\u2206Pod<\/jats:sup> mice develop an acute congenital nephrotic syndrome characterized by focal segmental glomerulosclerosis (FSGS) and proteinuria. <jats:italic>Podxl<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice, in contrast, have a normal lifespan, and fail to develop kidney disease under normal conditions. Intriguingly, although wild-type C57Bl\/6 mice are resistant to puromycin aminonucleoside (PA)-induced nephrosis (PAN), <jats:italic>Podxl<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice are highly sensitive and PA induces severe proteinuria and collapsing FSGS. In summary, we find that the developmental timepoint at which podocalyxin is ablated (immature vs. mature podocytes) has a profound effect on the urinary phenotype due to its critical roles in both the formation and the maintenance of podocyte ultrastructure. In addition, <jats:italic>Podxl<\/jats:italic><jats:sup>\u2206Pod<\/jats:sup> and <jats:italic>Podxl<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice offer powerful new mouse models to evaluate early biomarkers of proteinuric kidney disease and to test novel therapeutics.<\/jats:p>","DOI":"10.1038\/s41598-020-64907-3","type":"journal-article","created":{"date-parts":[[2020,6,10]],"date-time":"2020-06-10T10:03:15Z","timestamp":1591783395000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Distinct Functional Requirements for Podocalyxin in Immature and Mature Podocytes Reveal Mechanisms of Human Kidney Disease"],"prefix":"10.1038","volume":"10","author":[{"given":"Ido","family":"Refaeli","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael R.","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alvin Ka-Wai","family":"Wong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei Lin Z.","family":"Bissonnette","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Calvin D.","family":"Roskelley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Wayne Vogl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean J.","family":"Barbour","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin S.","family":"Freedman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly M.","family":"McNagny","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,6,10]]},"reference":[{"issue":"10","key":"64907_CR1","doi-asserted-by":"publisher","first-page":"e108881","DOI":"10.1371\/journal.pone.0108881","volume":"9","author":"EJ Debruin","year":"2014","unstructured":"Debruin, E. J. et al. Podocalyxin regulates murine lung vascular permeability by altering endothelial cell adhesion. PloS one. 9(10), e108881 (2014).","journal-title":"PloS one."},{"issue":"Pt 22","key":"64907_CR2","doi-asserted-by":"publisher","first-page":"3683","DOI":"10.1242\/jcs.037507","volume":"121","author":"JS Nielsen","year":"2008","unstructured":"Nielsen, J. S. & McNagny, K. M. Novel functions of the CD34 family. J Cell Sci. 121(Pt 22), 3683\u201392 (2008).","journal-title":"J Cell Sci."},{"issue":"8","key":"64907_CR3","doi-asserted-by":"publisher","first-page":"1669","DOI":"10.1681\/ASN.2008070782","volume":"20","author":"JS Nielsen","year":"2009","unstructured":"Nielsen, J. S. & McNagny, K. M. The role of podocalyxin in health and disease. 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