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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Pathology A Study Section (PTHA)
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University of Arkansas for Medical Sciences
Internal Medicine/Medicine
Schools of Medicine
Little Rock
United States
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Seng, N S; Megyesi, J; Tarcsafalvi, A et al. (2016) Mimicking Cdk2 phosphorylation of Bcl-xL at Ser73 results in caspase activation and Bcl-xL cleavage. Cell Death Discov 2:
Megyesi, J; Tarcsafalvi, A; Seng, Nshl et al. (2016) Cdk2 phosphorylation of Bcl-xL after stress converts it to a pro-apoptotic protein mimicking Bax/Bak. Cell Death Discov 2:
Megyesi, Judit; Tarcsafalvi, Adel; Li, Shenyang et al. (2015) Increased expression of p21WAF1/CIP1 in kidney proximal tubules mediates fibrosis. Am J Physiol Renal Physiol 308:F122-30
Hodeify, Rawad; Megyesi, Judit; Tarcsafalvi, Adel et al. (2013) Gender differences control the susceptibility to ER stress-induced acute kidney injury. Am J Physiol Renal Physiol 304:F875-82
Price, Peter M; Hodeify, Rawad (2012) A possible mechanism of renal cell death after ischemia/reperfusion. Kidney Int 81:720-1
Hodeify, Rawad; Tarcsafalvi, Adel; Megyesi, Judit et al. (2011) Cdk2-dependent phosphorylation of p21 regulates the role of Cdk2 in cisplatin cytotoxicity. Am J Physiol Renal Physiol 300:F1171-9
Hodeify, Rawad; Megyesi, Judit; Tarcsafalvi, Adel et al. (2010) Protection of cisplatin cytotoxicity by an inactive cyclin-dependent kinase. Am J Physiol Renal Physiol 299:F112-20
Price, Peter M (2010) A role for novel cell-cycle proteins in podocyte biology. Kidney Int 77:660-1
Price, Peter M; Safirstein, Robert L; Megyesi, Judit (2009) The cell cycle and acute kidney injury. Kidney Int 76:604-13
Yu, Fang; Megyesi, Judit; Price, Peter M (2008) Cytoplasmic initiation of cisplatin cytotoxicity. Am J Physiol Renal Physiol 295:F44-52

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