title: Both cyclin I and p35 are required for maximal survival benefit of cyclin-dependent kinase 5 in kidney podocytes.
abstract: Cyclin-dependent kinase (Cdk)-5 is activated by both cyclin I and the noncyclin activator p35 in terminally differentiated cells such as kidney podocytes and neurons. Cyclin I and p35 are restricted to podocytes in the kidney, and each limit podocyte apoptosis by activating Cdk5. To determine whether both activators are necessary, or whether they serve backup roles, a double cyclin I-p35 null mouse was generated. Experimental glomerular disease characterized by podocyte apoptosis was then induced by administering an anti-podocyte antibody. The results showed that under nonstressed conditions double mutants had normal kidney structure and function and were indistinguishable from wild-type, cyclin I(-/-), or p35(-/-) mice. In contrast, when stressed with disease, podocyte apoptosis increased fourfold compared with diseased cyclin I(-/-) or p35(-/-) mice. This resulted in a more pronounced decrease in podocyte number, proteinuria, and glomerulosclerosis. Under normal states and nephritic states, levels for the prosurvival protein Bcl-2 were lower in double cyclin I(-/-) p35(-/-) mice than the other mice. Similarly, levels of Bcl-xL, another prosurvival member, were lower in normal and nephritic double cyclin I(-/-) p35(-/-) mice but similar to single-cyclin I(-/-) mice. Moreover, levels of ERK1/2 and MEK1/2 activation were lower in nephritic double cyclin I(-/-) p35(-/-) mice but similar to single-cyclin I(-/-) mice. The results demonstrate that the activators of Cdk5, p35, and cyclin I are not required for normal kidney function. However, they play pivotal coordinated roles in maintaining podocyte survival during stress states in disease.
authors.affiliation: Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA 98195-6521, USA.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Taniguchi
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Pippin
authors.forename: Henning
authors.initials: H
authors.lastname: Hagmann
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Krofft
authors.forename: Alice M
authors.initials: AM
authors.lastname: Chang
authors.forename: Jiong
authors.initials: J
authors.lastname: Zhang
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Terada
authors.forename: Paul
authors.initials: P
authors.lastname: Brinkkoetter
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Shankland
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000009:adverse effects; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D056749:Cyclin I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004195:Disease Models, Animal; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010770:Phosphotransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000888:Antibodies, Anti-Idiotypic; C494812:Bcl2l1 protein, mouse; C534757:Ccni protein, mouse; C492236:Cdk5r1 protein, mouse; D056749:Cyclin I; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2