Altered podocyte structure in GLEPP1 (Ptpro)-deficient mice associated with hypertension and low glomerular filtration rate
Bryan L. Wharram, … , Linda C. Samuelson, Roger C. Wiggins
Bryan L. Wharram, … , Linda C. Samuelson, Roger C. Wiggins
Published November 15, 2000
Citation Information: J Clin Invest. 2000;106(10):1281-1290. https://doi.org/10.1172/JCI7236.
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Article

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

Abstract

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 expected genotypic ratio of 1:2:1, indicating that the Ptpro–/– genotype does not lead to embryonic or neonatal lethality. Kidney and glomerular structure was normal at the gross and light microscopic levels. Scanning and transmission electron microscopy showed that Ptpro–/– mice had an amoeboid rather than the typical octopoid structure seen in the wild-type mouse podocyte and that there were blunting and widening of the minor (foot) processes in association with altered distribution of the podocyte intermediate cytoskeletal protein vimentin. Reduced filtration surface area in association with these structural changes was confirmed by finding reduced glomerular nephrin content and reduced glomerular filtration rate in Ptpro–/– mice. There was no detectable increase in the urine albumin excretion of Ptpro–/– mice. After removal of one or more kidneys, Ptpro–/– mice had higher blood pressure than did their wild-type littermates. These data support the conclusion that the GLEPP1 (Ptpro) receptor plays a role in regulating the glomerular pressure/filtration rate relationship through an effect on podocyte structure and function.

Authors

Bryan L. Wharram, Meera Goyal, Patrick J. Gillespie, Jocelyn E. Wiggins, David B. Kershaw, Lawrence B. Holzman, Robert C. Dysko, Thomas L. Saunders, Linda C. Samuelson, Roger C. Wiggins

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Figure 1

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(a) Structure of 5′ end of the mouse GLEPP1 gene showing the exon/intron...
(a) Structure of 5′ end of the mouse GLEPP1 gene showing the exon/intron arrangement in relation to the coding region for the NH2-terminal end of the GLEPP1 protein. Numbered boxes represent exons. Exon 3 is a putative designation pending sequencing of the 5′ region of the gene. The site of gene deletion so as to interrupt an exon, induce a frameshift, and introduce a stop codon is shown. The Ab-binding site, which is 3′ of the deletion, is also shown. (b) Diagrammatic illustrations of the region of the wild-type allele to be targeted (upper), the GLEPP1 gene-targeting vector (middle), and the predicted structure of the targeted allele (lower). Filled boxes correspond to exons 3–7 depicted in a. Sites for restriction enzymes used for constructing the targeting vector and Southern screening of ES cell clones are shown. Size and location of Southern probes are shown, including the 3′ external probe (#1), the 5′ internal probe (#2), and the neo probe (#3). Arrowheads denote sites for PCR primers used for genotype analysis of mice. The 3′ primer, denoted by an asterisk, is common to both the wild-type and targeted alleles.