Both cyclin I and p35 are required for maximal survival benefit of cyclin-dependent kinase 5 in kidney podocytes

作者：Taniguchi Yoshinori; Pippin Jeffrey W; Hagmann Henning; Krofft Ronald D; Chang Alice M; Zhang Jiong; Terada Yoshio; Brinkkoetter Paul; Shankland Stuart J^*

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2012, 302(9): F1161-F1171.

DOI：10.1152/ajprenal.00614.2011

• Cdk5
• podocyte, glomerulonephritis

Taniguchi Y, Pippin JW, Hagmann H, Krofft RD, Chang AM, Zhang J, Terada Y, Brinkkoetter P, Shankland SJ. Both cyclin I and p35 are required for maximal survival benefit of cyclin-dependent kinase 5 in kidney podocytes. Am J Physiol Renal Physiol 302: F1161-F1171, 2012. First published January 18, 2012; doi:10.1152/ajprenal.00614.2011.-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 wildtype, 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.

• 出版日期2012-5