Our long-term objective is to prevent and/or treat acute renal failure. We showed that activation of the gene for the p21 cyclin-dependent kinase (cdk) inhibitor ameliorated renal failure after cisplatin administration and renal ischemia/reperfusion. After these injuries, comparing p21(+/+) with p21(-/-) mice, there was significantly less cellular damage, including both necrosis and apoptosis, less functional kidney failure, and less mortality in the p21(+/+) population. The mechanism was directly dependent on the role of p21 as a regulator of the cell cycle. We now find that induction of p21 using an adenoviral vector before cisplatin exposure completely protected mouse kidney proximal tubule cells in vitro from cytotoxicity. Similarly, pretreatment of kidney cells with different pharmacologic cdk2 inhibitors or with a histone deacetylase (HDAC) inhibitor known to induce p21 was also protective. We extended these findings by showing that a cdk2 inhibitory drug, with a spectrum of activity similar to p21, also protected kidney function and cell morphology in vivo from cisplatin-induced renal injury. We hypothesize that cdk2 inhibitors protect kidney cells from cisplatin-induced toxicity by inhibiting cell death pathways activated by cisplatin exposure. Furthermore, we hypothesize that cdk2 inhibitors will be useful to prevent and treat acute renal failure. We have developed aims that will determine the mechanism of cdk inhibitor protection in vitro and in vivo and provide initial steps to utilize cdk inhibitors to ameliorate cisplatin-induced renal failure. Our first specific aim is to determine the mechanism of cdk inhibitor protection. We will confirm that cdk inhibitor protection is dependent on repressing cdk2 activity. We will determine cdk2 localization and the localization of cdk2-p21 interaction. We will determine the cell death pathway(s) inhibited by cdk2 inhibitors, and for each death pathway inhibited by cdk2 inhibitors, determine whether it is activated by cisplatin. Our second specific aim is to determine conditions and mechanisms of protection by cdk2 inhibitors in vivo. We will determine whether cdk2 knock-out mice are protected from cisplatin nephrotoxicity, and whether the samefragment of p21 that protects in vitro also protects in vivo. We will confirm purvalanol in vivo protection and refine the conditions for its action.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Rys-Sikora, Krystyna E
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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
Price, Peter M (2010) A role for novel cell-cycle proteins in podocyte biology. Kidney Int 77:660-1
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; 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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