title: Complement-mediated glomerular injury is reduced by inhibition of protein-tyrosine phosphatase 1B.
abstract: The unfolded protein response and endoplasmic reticulum-associated degradation (ERAD) contribute to injury in renal glomerular diseases, including those mediated by complement C5b-9. In the present study, we address the role of protein-tyrosine phosphatase 1B (PTP1B) in complement-mediated glomerular injury and ERAD. In glomerular epithelial cells (GECs)/podocytes and PTP1B-deficient mouse embryonic fibroblasts exposed to complement, inhibition/deletion of PTP1B reduced ERAD, as monitored by the ERAD reporter CD3δ. Overexpression of PTP1B produced an effect similar to PTP1B deficiency on ERAD in complement-treated GECs. Complement-mediated cytotoxicity was reduced after PTP1B overexpression and tended to be reduced after PTP1B inhibition. PTP1B enhanced the induction of certain ERAD components via the inositol-requiring-1α branch of the unfolded protein response. PTP1B knockout mice with anti-glomerular basement membrane glomerulonephritis had decreased proteinuria and showed less podocyte loss and endoplasmic reticulum dysfunction compared with wild-type littermates. These results imply that endogenous levels of PTP1B are tightly regulated and that both overexpression and inhibition can affect ERAD. The cytoprotective effects of PTP1B deletion in cultured cells and in anti-glomerular basement membrane nephritis suggest that PTP1B may potentially be a therapeutic target in complement-mediated diseases.
authors: Department of Medicine and Biochemistry, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
authors: Lisa
authors: L
authors: Nezvitsky
authors: Department of Medicine and Biochemistry, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
authors: Michel L
authors: ML
authors: Tremblay
authors: Department of Medicine and Biochemistry, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
authors: Tomoko
authors: T
authors: Takano
authors: Department of Medicine and Biochemistry, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
authors: Joan
authors: J
authors: Papillon
authors: Department of Medicine and Biochemistry, McGill University Health Centre, McGill University, Montreal, Quebec, Canada andrey.cybulsky@mcgill.ca.
authors: Andrey V
authors: AV
authors: Cybulsky
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000494:pharmacology / Q000502:physiology*; D004195:Disease Models, Animal; D060746:Endoplasmic Reticulum-Associated Degradation / Q000187:drug effects / Q000502:physiology*; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D005921:Glomerulonephritis / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050199:Podocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology; D051381:Rats; D056811:Unfolded Protein Response / Q000502:physiology
chemical_list: D003165:Complement System Proteins; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; C516610:Ptpn1 protein, rat
keywords: cytotoxicity; endoplasmic reticulum; podocytes