RENAL TUBULE REGENERATION AFTER ISCHEMIC-INJURY IS COUPLED TO THE UP-REGULATION AND ACTIVATION OF CYCLINS AND CYCLIN-DEPENDENT KINASES

Proliferation of renal tubules after acute injury is a reactive proces s of renal regeneration for recovery of renal function. Molecular and cellular mechanisms of the re-entrance of renal cells into the cell cy cle after injury remain largely unknown. We have measured the correlat ions among the extent of proliferative activity and expression of cycl ins and CDKs, and activity of each CDK during the regeneration period in the outer medullae of kidneys after ischemic injury in rats. The ra tio of proliferating cell nuclear antigen (PCNA) positively immune-sta ined nuclei to total nuclei per each section of the outer medulla of k idney 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%), remai ned at a plateau at days 3 and 5 (30.5 and 32.3%), and decreased at da y 7 and day 14 (17.3 and 12.2%) after ischemic injury. Proliferative a ctivity was readily detectable in renal tubules, but was hardly detect able 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, t he protein levels of CDK4 and CDK2, and the activities of CDKs (CDK4, CDK2 and cdc2) increased in the outer medullae of kidneys after ischem ic injury. These findings suggest that the temporal induction of proli ferative activity in outer medullary tubules was closely linked with t he cyclin/CDK system for regeneration of kidney after ischemic injury.