Altered podocyte structure in GLEPP1 (Ptpro)-deficient mice associated with hypertension and low glomerular filtration rate

Glomerular epithelial protein 1 (GLEPP1) is a receptor tyrosine phosphatase present on the apical cell surface of the glomerular podocyte. The GLEPP1 gene (Ptpro) was disrupted at an exon coding for the NH2-terminal region by gene targeting in embryonic stem cells. Heterozygote mating produced the e xpected genotypic ratio of 1:2:1, indicating that the Ptpro(-/-) genotype d oes not lead to embryonic or neonatal lethality. Kidney and glomerular stru cture was normal at the gross and Light microscopic levels. Scanning and tr ansmission electron microscopy showed that Ptpro(-/-) mice had an amoeboid rather than the typical octopoid structure seen in the wild-type mouse podo cyte and that there were blunting and widening of the minor (foot) processe s in association with altered distribution of the podocyte intermediate cyt oskeletal protein vimentin. Reduced filtration surface area in association with these structural changes was confirmed by finding reduced glomerular n ephrin content and reduced glomerular filtration rate in Ptpro(-/-) mice. T here was no detectable increase in the urine albumin excretion of Ptpro(-/- ) mice. After removal of one or more kidneys, Ptpro(-/-) mice had higher bl ood pressure than did their wild-type littermates. These data support the c onclusion that the GLEPP1 (Ptpro) receptor plays a role in regulating the g lomerular pressure/filtration rate relationship through an effect on podocy te structure and function.