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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.

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