Distinct Functional Requirements for Podocalyxin in Immature and Mature Podocytes Reveal Mechanisms of Human Kidney Disease.

Abstract

Dominant and recessive mutations in podocalyxin (PODXL) are associated with human kidney disease. Interestingly, some PODXL mutations manifest as anuria while others are associated with proteinuric kidney disease. PODXL 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 PODXL contribute to these disparate disease pathologies. Here we generated two mouse stains: one that deletes Podxl in developmentally mature podocytes (Podxl∆Pod) and a second that is heterozygous for podocalyxin in all tissues (Podxl+/-). 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 (Podxl-/-), which die shortly after birth from anuria and hypertension, Podxl∆Pod mice develop an acute congenital nephrotic syndrome characterized by focal segmental glomerulosclerosis (FSGS) and proteinuria. Podxl+/- 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), Podxl+/- 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, Podxl∆Pod and Podxl+/- mice offer powerful new mouse models to evaluate early biomarkers of proteinuric kidney disease and to test novel therapeutics.

• Authors: Ido Refaeli, Michael R Hughes, Alvin Ka-Wai Wong, Mei Lin Z Bissonnette, Calvin D Roskelley, A Wayne Vogl, Sean J Barbour, Benjamin S Freedman, Kelly M McNagny
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 9419 (06 10 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 32523052 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Sialoglycoproteins
• podocalyxin
• Puromycin Aminonucleoside

Topics

• Animals
• Female
• Glomerulosclerosis, Focal Segmental (metabolism, pathology)
• Heterozygote
• Humans
• Kidney Diseases (metabolism, pathology)
• Kidney Glomerulus (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nephrotic Syndrome (metabolism, pathology)
• Phenotype
• Podocytes (metabolism, pathology)
• Proteinuria (metabolism, pathology)
• Puromycin Aminonucleoside (metabolism)
• Sialoglycoproteins (metabolism)