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.
Highlights
Podocalyxin is a single-pass transmembrane sialomucin whose expression in the kidney is restricted to the surface of podocytes and vascular endothelial cells[1]
To better clarify the contribution of Podxl mutations to mature podocyte function, we have conditionally deleted Podxl from terminally differentiated, capillary loop stage (CLS) mouse podocytes. We find that these (Podxl∆Pod) mice survive to approximately 3–7 weeks of age and present with severe proteinuria, focal segmental glomerulosclerosis (FSGS), effacement of podocyte foot processes and a failure to target apical and basal proteins to the appropriate cellular domain
We addressed the role of podocalyxin in mature podocytes
Summary
Podocalyxin (human: PODXL; mouse: Podxl) is a single-pass transmembrane sialomucin whose expression in the kidney is restricted to the surface of podocytes and vascular endothelial cells[1]. Compound heterozygous null mutations in human PODXL lead to a congenital nephrotic syndrome and anuria similar to that observed in Podxl null mice[13] Beyond this early developmental role for Podxl in podocyte morphogenesis, whether or not it directly serves additional functions in mature podocytes and is dysfunctional in adult renal disease remains to be determined. Podxl+/− mice have no obvious renal phenotype at steady state, but are highly susceptible to chemically-induced nephrosis and phenocopy the pathology observed in patients with adult-onset collapsing FSGS These later findings provide support of a two-hit mechanism (one genetic and one environmental) in the onset of adult FSGS, and highlight the Podxl+/− mouse strain as a novel model for the development of biomarkers of FSGS and as a screening tool for the preclinical evaluation of therapeutics for proteinuric kidney disease
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