Renal tubule regeneration after ischemic injury is coupled to the up-regulation and activation of cyclins and cyclin dependent kinases

Abstract

Proliferation of renal tubules after acute injury is a reactive process of renal regeneration for recovery of renal function. Molecular and cellular mechanisms of the re-entrance of renal cells into the cell cycle after injury remain largely unknown. We have measured the correlations among the extent of proliferative activity and expression of cyclins and CDKs, and activity of each CDK during the regeneration period in the outer medullae of kidneys after ischemic injury in rats. The ratio of proliferating cell nuclear antigen (PCNA) positively immuno-stained nuclei to total nuclei per each section of the outer medulla of kidney indicated the proliferative index (PI) for this study. PI in the control period was 0.1%. The PI was increased at day 1 (13.4%), remained at a plateau at days 3 and 5 (30.5 and 32.3%), and decreased at day 7 and day 14 (17.3 and 12.2%) after ischemic injury. Proliferative activity was readily detectable in renal tubules, but was hardly detectable in glomeruli or blood vessels. As the PI increased, the mRNA and protein levels of cyclins D1, D3 and B, the mRNA levels of cyclin A, the protein levels of CDK4 and CDK2, and the activities of CDKs (CDK4, CDK2 and cdc2) increased in the outer medullae of kidneys after ischemic injury. These findings suggest that the temporal induction of proliferative activity in outer medullary tubules was closely linked with the cyclin/CDK system for regeneration of kidney after ischemic injury.