title: Cyclin-dependent kinase 2 protects podocytes from apoptosis.
abstract: Loss of podocytes is an early feature of diabetic nephropathy (DN) and predicts its progression. We found that treatment of podocytes with sera from normoalbuminuric type 1 diabetes patients with high lipopolysaccharide (LPS) activity, known to predict progression of DN, downregulated CDK2 (cyclin-dependent kinase 2). LPS-treatment of mice also reduced CDK2 expression. LPS-induced downregulation of CDK2 was prevented in vitro and in vivo by inhibiting the Toll-like receptor (TLR) pathway using immunomodulatory agent GIT27. We also observed that CDK2 is downregulated in the glomeruli of obese Zucker rats before the onset of proteinuria. Knockdown of CDK2, or inhibiting its activity with roscovitine in podocytes increased apoptosis. CDK2 knockdown also reduced expression of PDK1, an activator of the cell survival kinase Akt, and reduced Akt phosphorylation. This suggests that CDK2 regulates the activity of the cell survival pathway via PDK1. Furthermore, PDK1 knockdown reduced the expression of CDK2 suggesting a regulatory loop between CDK2 and PDK1. Collectively, our data show that CDK2 protects podocytes from apoptosis and that reduced expression of CDK2 associates with the development of DN. Preventing downregulation of CDK2 by blocking the TLR pathway with GIT27 may provide a means to prevent podocyte apoptosis and progression of DN.
authors.affiliation: Department of Pathology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Pauliina
authors.initials: P
authors.lastname: Saurus
authors.affiliation: Department of Pathology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Sara
authors.initials: S
authors.lastname: Kuusela
authors.affiliation: Department of Pathology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Dumont
authors.affiliation: Department of Pathology, University of Helsinki, 00290 Helsinki, Finland.|Laboratory Animal Centre, University of Helsinki, 00290 Helsinki Finland.
authors.forename: Eero
authors.initials: E
authors.lastname: Lehtonen
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, University of Helsinki, 00014 Helsinki, Finland.|Division of Nephrology, Helsinki University Hospital, 00290 Helsinki, Finland.|Diabetes &Obesity Research Program, Research Program´s Unit, 00014 University of Helsinki, Finland.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Fogarty
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, University of Helsinki, 00014 Helsinki, Finland.|Division of Nephrology, Helsinki University Hospital, 00290 Helsinki, Finland.|Diabetes &Obesity Research Program, Research Program´s Unit, 00014 University of Helsinki, Finland.
authors.forename: Mariann I
authors.initials: MI
authors.lastname: Lassenius
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, University of Helsinki, 00014 Helsinki, Finland.|Division of Nephrology, Helsinki University Hospital, 00290 Helsinki, Finland.|Diabetes &Obesity Research Program, Research Program´s Unit, 00014 University of Helsinki, Finland.
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, University of Helsinki, 00014 Helsinki, Finland.|Division of Nephrology, Helsinki University Hospital, 00290 Helsinki, Finland.|Diabetes &Obesity Research Program, Research Program´s Unit, 00014 University of Helsinki, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Lehto
authors.affiliation: University of Bristol, Bristol Royal Hospital for Children, BS2 8BJ Bristol, United Kingdom.
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, University of Helsinki, 00014 Helsinki, Finland.|Division of Nephrology, Helsinki University Hospital, 00290 Helsinki, Finland.|Diabetes &Obesity Research Program, Research Program´s Unit, 00014 University of Helsinki, Finland.|Baker IDI Heart &Diabetes Institute, VIC 3004 Melbourne, Australia.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.affiliation: Department of Pathology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Lehtonen
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D006801:Humans; D008810:Mice, Inbred C57BL; D050199:Podocytes / Q000201:enzymology* / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011924:Rats, Zucker
chemical_list: C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; C000631434:Pdk1 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases; D051357:Cyclin-Dependent Kinase 2