title: Protein tyrosine phosphatase 1B inhibition protects against podocyte injury and proteinuria.
abstract: Protein tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed nonreceptor protein-tyrosine phosphatase that regulates various cellular functions, including migration. Recent studies suggest that an increased migratory phenotype of podocytes may be responsible for proteinuria and foot process effacement. The current study addresses the role of PTP1B in podocyte injury and proteinuria. PTP1B was markedly up-regulated in the glomerulus, notably in podocytes, in three rodent models of podocyte injury. Podocyte-specific ablation of the PTP1B gene ameliorated proteinuria induced by lipopolysaccharide and Adriamycin (doxorubicin). The use of a specific PTP1B inhibitor also protected against lipopolysaccharide-induced proteinuria. In contrast, podocyte-specific PTP1B transgenic male mice developed spontaneous proteinuria and foot process effacement. In cultured mouse podocytes, PTP1B knockdown and/or pretreatment with the PTP1B inhibitor blunted lipopolysaccharide-induced cell migration, activation of Src-family kinases (SFKs), and phosphorylation of focal adhesion kinase at Y397 (pFAK(Y397)), the latter being crucial for cell migration. Lipopolysaccharide-injected mice showed increased glomerular expression of active SFKs and pFAK(Y397), both of which were inhibited by podocyte-specific PTP1B knockout and the PTP1B inhibitor. Moreover, podocyte-specific PTP1B transgenic mice showed increased glomerular expression of active SFKs and pFAK(Y397). In summary, PTP1B up-regulation in podocytes induces a migratory response by activating SFKs and FAK, leading to foot process effacement and proteinuria. Pharmacological inhibition of PTP1B may have therapeutic potential in the treatment of proteinuric diseases.
authors.affiliation: Division of Nephrology, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kumagai
authors.affiliation: Division of Nephrology, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Cindy
authors.initials: C
authors.lastname: Baldwin
authors.affiliation: Division of Nephrology, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Lamine
authors.initials: L
authors.lastname: Aoudjit
authors.affiliation: Division of Nephrology, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Nezvitsky
authors.affiliation: Division of Nephrology, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Robins
authors.affiliation: Division of Nephrology, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Division of Nephrology, Department of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address: tomoko.takano@mcgill.ca.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takano
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009401:Nephrosis; D010766:Phosphorylation; D050199:Podocytes / Q000201:enzymology / Q000473:pathology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D011507:Proteinuria / Q000201:enzymology / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse