Cyclin-dependent kinase 2 protects podocytes from apoptosis

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Saurus , P , Kuusela , S , Dumont , V , Lehtonen , E , Fogarty , C L , Lassenius , M I , Forsblom , C , Lehto , M , Saleem , M A , Groop , P-H & Lehtonen , S 2016 , ' Cyclin-dependent kinase 2 protects podocytes from apoptosis ' , Scientific Reports , vol. 6 , 21664 .

Title: Cyclin-dependent kinase 2 protects podocytes from apoptosis
Author: Saurus, Pauliina; Kuusela, Sara; Dumont, Vincent; Lehtonen, Eero; Fogarty, Christopher L.; Lassenius, Mariann I.; Forsblom, Carol; Lehto, Markku; Saleem, Moin A.; Groop, Per-Henrik; Lehtonen, Sanna
Contributor organization: Sanna Lehtonen research group
Department of Pathology
KEK Meilahti
Department of Medical and Clinical Genetics
Nefrologian yksikkö
Diabetes and Obesity Research Program
Department of Medicine
Research Programs Unit
Per Henrik Groop / Principal Investigator
Date: 2016-02-15
Language: eng
Number of pages: 14
Belongs to series: Scientific Reports
ISSN: 2045-2322
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.
3111 Biomedicine
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion

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