CYCLIN DEPENDENT KINASE INHIBITOR IN ACUTE RENAL FAILURE

University Of Arkansas Med Scis Ltl Rock, Little Rock AR

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Abstract

This application is directed towards the study of p21, a cyclin- dependent kinase inhibitor in acute renal failure. The Principal Investigator has found that in three different types of acute renal injury, namely, ischemia reperfusion, cisplatin administration, and ureteral obstruction, there is rapid and profound induction in renal tubules of p21, a cyclin-dependent kinase inhibitor, which has pleiotropic effects on cell fate, including cell-cycle interruption, induction of cellular senescence, termination differentiation and inhibition of regeneration. The Principal Investigator provides evidence that p21 may serve a protective role in acute renal failure. This view is based on studies using a p21 null mouse subjected to cisplatin nephrotoxicity. The wild type p21 mouse as compared to the p21 null mouse demonstrated markedly reduced necrosis and apoptosis, less histologic injury and greater preservation of renal function in conjunction with less mortality from acute renal failure. In the wild type mouse, proximal tubular necrosis mainly involved the S3 segment whereas in the p21 null mouse, such necrosis had extended through all segments. The induction of p21 is observed not only in the cisplatin model, but also in ischemia reperfusion injury as well as urinary tract obstruction. In the cisplatin model, there is also intense induction of p53, a finding that is not observed in the other models. Since p53 is known to include p21, the principal investigator hypothesizes that renal injury per se, and in some instances, complemented by induction of p53 as occurs in cisplatin nephropathy, represents an adaptive response to renal injury. This induction of p21 has a protective effect in renal injury since it prevents the progression of cells from the G1 phase to the S phase. That prevention of progression from G1 to S allow reparative responses to occur such that the entry of cells with damaged DNA into the S phase does not occur. In the latter circumstance, when there is an absence of p21 the entry of cells into the S phase leads to the induction of necrosis and apoptosis because of unrepaired and damaged DNA. The cell death resulting from such DNA injury in turn leads to a commensurate proliferative response. Thus, p21, in essence, prevents both the proliferation and cell death which is more manifest in the p21 null mouse.