title: Podocyte apoptosis is prevented by blocking the Toll-like receptor pathway.
abstract: High serum lipopolysaccharide (LPS) activity in normoalbuminuric patients with type 1 diabetes (T1D) predicts the progression of diabetic nephropathy (DN), but the mechanisms behind this remain unclear. We observed that treatment of cultured human podocytes with sera from normoalbuminuric T1D patients with high LPS activity downregulated 3-phosphoinositide-dependent kinase-1 (PDK1), an activator of the Akt cell survival pathway, and induced apoptosis. Knockdown of PDK1 in cultured human podocytes inhibited antiapoptotic Akt pathway, stimulated proapoptotic p38 MAPK pathway, and increased apoptosis demonstrating an antiapoptotic role for PDK1 in podocytes. Interestingly, PDK1 was downregulated in the glomeruli of diabetic rats and patients with type 2 diabetes before the onset of proteinuria, further suggesting that reduced expression of PDK1 associates with podocyte injury and development of DN. Treatment of podocytes in vitro and mice in vivo with LPS reduced PDK1 expression and induced apoptosis, which were prevented by inhibiting the Toll-like receptor (TLR) signaling pathway with the immunomodulatory agent GIT27. Our data show that LPS downregulates the cell survival factor PDK1 and induces podocyte apoptosis, and that blocking the TLR pathway with GIT27 may provide a non-nephrotoxic means to prevent the progression of DN.
authors.affiliation: Department of Pathology, University of Helsinki, Helsinki, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Saurus
authors.affiliation: Department of Pathology, University of Helsinki, Helsinki, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Kuusela
authors.affiliation: 1] Department of Pathology, University of Helsinki, Helsinki, Finland [2] Laboratory Animal Centre, University of Helsinki, Helsinki, Finland.
authors.forename: E
authors.identifier: 0000000341892415
authors.initials: E
authors.lastname: Lehtonen
authors.affiliation: Department of Pathology, University of Helsinki, Helsinki, Finland.
authors.forename: M E
authors.initials: ME
authors.lastname: Hyvönen
authors.affiliation: Department of Pathology, University of Helsinki, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Ristola
authors.affiliation: 1] Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland [2] Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland [3] Diabetes and Obesity Research Program, Research Program's Unit, University of Helsinki, Helsinki, Finland.
authors.forename: C L
authors.initials: CL
authors.lastname: Fogarty
authors.affiliation: Department of Pathology, HUSLAB and Helsinki University Hospital, Helsinki and Hyvinkää, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Tienari
authors.affiliation: 1] Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland [2] Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland [3] Diabetes and Obesity Research Program, Research Program's Unit, University of Helsinki, Helsinki, Finland.
authors.forename: M I
authors.initials: MI
authors.lastname: Lassenius
authors.affiliation: 1] Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland [2] Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland [3] Diabetes and Obesity Research Program, Research Program's Unit, University of Helsinki, Helsinki, Finland.
authors.forename: C
authors.initials: C
authors.lastname: Forsblom
authors.affiliation: 1] Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland [2] Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland [3] Diabetes and Obesity Research Program, Research Program's Unit, University of Helsinki, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Lehto
authors.affiliation: Bristol Royal Hospital for Children, University of Bristol, Bristol, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: 1] Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland [2] Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland [3] Diabetes and Obesity Research Program, Research Program's Unit, University of Helsinki, Helsinki, Finland [4] Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: P-H
authors.initials: PH
authors.lastname: Groop
authors.affiliation: Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Holthöfer
authors.affiliation: Department of Pathology, University of Helsinki, Helsinki, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Lehtonen
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood; D006801:Humans; D008070:Lipopolysaccharides / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010080:Oxazoles / Q000494:pharmacology; D050199:Podocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C518641:3-phenyl-4,5-dihydro-5-isoxazole acetic acid; D000085:Acetates; D008070:Lipopolysaccharides; D010080:Oxazoles; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; C000631434:Pdk1 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051193:Toll-Like Receptors; D017346:Protein Serine-Threonine Kinases