Abstract

Cyclin-dependent kinase 5 (Cdk5) is expressed in terminally differentiated cells, where it drives development, morphogenesis, and survival. Temporal and spatial kinase activity is regulated by specific activators of Cdk5, dependent on the cell type and environmental factors. In the kidney, Cdk5 is exclusively expressed in terminally differentiated glomerular epithelial cells called podocytes. In glomerular disease, signaling mechanisms via Cdk5 have been addressed by single or combined conventional knockout of known specific activators of Cdk5. A protective, anti-apoptotic role has been ascribed to Cdk5 but not a developmental phenotype, as in terminally differentiated neurons. The effector kinase itself has never been addressed in animal models of glomerular disease. In the present study, conditional and inducible knockout models of Cdk5 were analyzed to investigate the role of Cdk5 in podocyte development and glomerular disease. While mice with podocyte-specific knockout of Cdk5 had no developmental defects and regular lifespan, loss of Cdk5 in podocytes increased susceptibility to glomerular damage in the nephrotoxic nephritis model. Glomerular damage was associated with reduced anti-apoptotic signals in Cdk5-deficient mice. In summary, Cdk5 acts primarily as master regulator of podocyte survival during glomerular disease and—in contrast to neurons—does not impact on glomerular development or maintenance.

Highlights

  • The atypical cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase with prime functions in terminally differentiated cell types [1]

  • Cdk5 expression was determined by qPCR on samples of primary podocytes isolated from mice carrying heterozygous hNPHS.Cre and homozygous Cdk5-floxed (Cdk5pko ), heterozygous Cdk5-floxed (Cdk5het ), or homozygous

  • Cdk5 expression was determined by qPCR on samples of primary podocytes isolated from mice carrying heterozygous hNPHS.Cre and homozygous Cdk5-floxed (Cdk5pko), heterozygous Cdk5-floxed (Cdk5het), or homozygous wild wt) alleles

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Summary

Introduction

The atypical cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase with prime functions in terminally differentiated cell types [1]. Cdk is a crucial regulator of brain development and morphological characteristics, including neuronal migration, axonal guidance, and synapse formation and plasticity, as well as cytoskeletal rearrangement. The kinase is activated by specific activators, such as p35, p25, p39, and cyclin I, and inhibited by GSTP1, cyclin D1, and cyclin E [6,7,8,9,10,11]. These activators and inhibitors confer a tight spatial and temporal regulation of Cdk activity [12,13,14]. The conventional knockout of Cdk is associated with severe structural lesions of the central nervous system and perinatal mortality [15]

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