The p21 protein is found in the nucleus of most cells at low levels and is induced to elevated levels after DNA damage, causing cell-cycle arrest. We have reported that p21 mRNA is rapidly induced to high levels in murine kidney after acute renal failure. The function(s) in the kidney of p21 induction in cisplatin-induced acute renal failure was studied with mice that are homozygous for a p21 gene deletion. After drug administration, as compared with their wild-type littermates, p21(-/-) mice display a more rapid onset of the physiologic signs of acute renal failure, develop more severe morphologic damage, and have a higher mortality. Therefore, the induction of p21 after cisplatin administration is a protective event for kidney cells. Using both bromodeoxyuridine incorporation and nuclear proliferating cell nuclear antigen detection, we found that cisplatin administration caused kidney cells to start entering the cell-cycle. However, cell-cycle progression is inhibited in wild-type mice, whereas kidney cells in the p21(-/-) mice progress into S-phase. We propose that p21 protects kidneys damaged by cisplatin by preventing DNA-damaged cells from entering the cell-cycle, which would otherwise result in death from either apoptosis or necrosis.

Cisplatin, a widely used chemotherapy drug, induces acute kidney injury, which limits its use and efficacy in cancer treatment. However, the molecular mechanism of cisplatin-induced nephrotoxicity is currently unclear. Using pharmacological and gene knockout models, we now demonstrate a pathological role for p53 in cisplatin nephrotoxicity. In C57BL/6 mice, cisplatin treatment induced p53 phosphorylation and protein accumulation, which was accompanied by the development of acute kidney injury. p53 was induced in both proximal and distal tubular cells and partially colocalized with apoptosis. Pifithrin-alpha, a pharmacological inhibitor of p53, suppressed p53 activation and ameliorated kidney injury during cisplatin treatment. Moreover, cisplatin-induced nephrotoxicity was abrogated in p53-deficient mice. Compared with wild-type animals, p53-deficient mice showed a better renal function, less tissue damage, and fewer apoptotic cells. In addition, cisplatin induced less apoptosis in proximal tubular cells isolated from p53-deficient mice than the cells from wild-type animals. Together these results suggest the involvement of p53 in cisplatin-induced renal cell apoptosis and nephrotoxicity.

No abstract

Acute kidney injury (AKI) activates pathways of cell death and cell proliferation. Although seemingly discrete and unrelated mechanisms, these pathways can now be shown to be connected and even to be controlled by similar pathways. The dependence of the severity of renal-cell injury on cell cycle pathways can be used to control and perhaps to prevent acute kidney injury. This review is written to address the correlation between cellular life and death in kidney tubules, especially in acute kidney injury.

Cisplatin treatment induces extensive death of the proximal tubules in mice. We also demonstrated that treatment of immortalized mouse proximal tubule cells (TKPTS) with 25 microM cisplatin induces apoptotic death in vitro. Here, we demonstrate that members of the MAPKs such as ERK, JNK, and p38 are all activated after cisplatin treatment both in vivo and in vitro. Because MAPKs mediate cell survival and death, we studied their role in cisplatin-induced cell death in vitro. Apoptosis was confirmed by cell morphology, fluorescence-activated cell-sorting analysis, annexin V/propidium iodide binding, and caspase-3 activation in TKPTS cells. Inhibition of ERK, but not JNK or p38, abolished caspase-3 activation and apoptotic death, suggesting a prodeath role of ERK in cisplatin-induced injury. We also determined that cisplatin-induced ERK as well as caspase-3 activation are epidermal growth factor receptor (EGFR) and c-src dependent because inhibition of these genes inhibited ERK and caspase-3 activation and attenuated apoptotic death. These results suggest that caspase-3 mediates cisplatin-induced cell death in TKPTS cells via an EGFR/src/ERK-dependent pathway. We also suggest that the prodeath effect of ERK is injury type dependent because during oxidant injury, ERK supports survival rather than death in the same cells. We propose that injury-specific outcome diverges downstream from ERK in cisplatin- or H(2)O(2)-mediated cell survival and death.

No abstract

In three different models of acute renal failure (ischemia, ureteral obstruction, and cisplatin administration), the p21WAF1/CIP1/SDI1 gene, the protein product of which is associated with cell-cycle interruption, terminal differentiation, and cellular senescence, was activated in murine kidney cells. This transcription was localized in kidney only to cells of thick ascending limbs and distal convoluted tubules. Although the tumor suppressor protein, p53, can trans-activate the p21 gene in some cells, increased levels of nuclear p53 protein could be demonstrated only in the cisplatin model of acute renal failure. High levels of p21 mRNA were induced in kidney of p53 "null" mice, demonstrating that p21 gene activation was through a p53-independent pathway. We also present evidence that, in the cisplatin model, both p53-independent and p53-dependent induction of p21 mRNA occur simultaneously. We conclude that p21 gene activation is a general response to renal injury and could be a key determinant of cell fate in the cell in which it is expressed.

Recovery from ischemic renal injury is accompanied by enhanced DNA synthesis and a typical immediate early (IE) gene response. These two processes occur in distinct cell populations, suggesting that the IE gene response does not serve a proliferative function directly. As cellular stress induces an IE response through activation of the stress-activated protein kinases (SAPK) that is not proliferative and can be inhibited by N-acetyl-L-cysteine (NAC), we determined whether the Jun NH2-terminal kinases (JNK), members of the SAPKs, are activated during ischemia and whether NAC administration reduces the IE response and/or the induction of JNK activity. NAC (6 mM/kg body wt) infused 1 h prior to and 1 h following renal ischemia reduced c-fos and c-jun expression by 50 and 70%, respectively. Ischemia increased JNK activity, and this increase was inhibited by NAC. NAC infused animals had a higher glomerular filtration rate at 1 day (NAC, 0.9 +/- 0.2, vs. control, 0.05 +/- 0.01 ml/min, P < 0.001) and 7 days (NAC, 2.0 +/- 0.1, vs. control, 1.2 +/- 0.1, P < 0.001) after the induction of ischemia. NAC did not reduce the extent of proximal tubule necrosis at 24 h after reperfusion but improved histological appearance of the kidney at 7 days. The mechanism by which NAC ameliorates the loss of renal function is unknown but may involve its general properties as an antioxidant or a possible interaction with NAC and NO. We conclude that the IE gene response of the kidney to ischemia reperfusion is a consequence of the stress-activated kinase pathway and that part of the response is deleterious to kidney function and cellular integrity.