APOBEC-1 deletion enhances cisplatin-induced acute kidney injury.

Cisplatin (CP) induces acute kidney injury (AKI) whereby proximal tubules undergo regulated necrosis. Repair is almost complete after a single dose. We now demonstrate a role for Apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (Apobec-1) that is prominently expressed at the interface between acute and chronic kidney injury (CKD), in the recovery from AKI.

AMP-activated protein kinase contributes to cisplatin-induced renal epithelial cell apoptosis and acute kidney injury.

Cisplatin, a commonly used anticancer drug, has been shown to induce acute kidney injury, which limits its clinical use in cancer treatment. Emerging evidence has suggested that AMP-activated protein kinase (AMPK), which functions as a cellular energy sensor, is activated by various cellular stresses that deplete cellular ATP. However, the potential role of AMPK in cisplatin-induced apoptosis of renal tubular epithelial cells has not been studied.

TAK1 deficiency attenuates cisplatin-induced acute kidney injury.

Cisplatin can cause acute kidney injury (AKI), but the molecular mechanisms are not well understood. The objective of the present study was to examine the role of transforming growth factor-β-activated kinase-1 (TAK1) in the pathogenesis of cisplatin-induced AKI. Wild-type mice and proximal tubule TAK1-deficient mice were treated with vehicle or cisplatin.

Cdk2-dependent phosphorylation of p21 regulates the role of Cdk2 in cisplatin cytotoxicity.

Cisplatin cytotoxicity is dependent on cyclin-dependent kinase 2 (Cdk2) activity in vivo and in vitro. We found that an 18-kDa protein identified by mass spectrometry as p21(WAF1/Cip1) was phosphorylated by Cdk2 starting 12 h after cisplatin exposure. The analysis showed it was phosphorylated at serine 78, a site not previously identified.

Am I my brother's keeper?: fratricide in the kidney.

Experimental acute kidney injury (AKI) is accompanied by the death of renal tubule epithelial cells, necrosis and apoptosis of the terminal portion of the proximal tubule, and apoptosis in the distal nephron. While immune competent cells invading the kidney play a role in such cell death, intervention in these processes only partially ameliorates the extent of cell death. Given the results of Linkermann et al.

Chronic kidney disease and GWAS: "the proper study of mankind is man".

Genome-wide association studies (GWAS) have been applied to complex diseases such as diabetes and hypertension, successfully uncovering strong gene associations of potential pathophysiologic significance. Recently, two studies (Köttgen et al., 2010; Chambers et al.

Protection of cisplatin cytotoxicity by an inactive cyclin-dependent kinase.

Cisplatin cytotoxicity is dependent on cyclin-dependent kinase 2 (Cdk2) activity in vivo and in vitro. A Cdk2 mutant (Cdk2-F80G) was designed in which the ATP-binding pocket was altered. When expressed in mouse kidney cells, this protein was kinase inactive, did not inhibit endogenous Cdk2, but protected from cisplatin.

Deletion of LOX-1 attenuates renal injury following angiotensin II infusion.

Angiotensin II upregulates the expression of LOX-1, a recently identified oxidized low-density lipoprotein receptor controlled by redox state which in turn upregulates angiotensin II activity on its activation. To test whether interruption of this positive feedback loop might reduce angiotensin II-induced hypertension and subsequent renal injury, we studied LOX-1 knockout mice. After infusion with angiotensin II for 4 weeks systolic blood pressure gradually increased in the wild-type mice; this rise was significantly attenuated in the LOX-1 knockout mice.

The cell cycle and acute kidney injury.

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.

p66shc inhibits pro-survival epidermal growth factor receptor/ERK signaling during severe oxidative stress in mouse renal proximal tubule cells.

The fully executed epidermal growth factor receptor (EGFR)/Ras/MEK/ERK pathway serves a pro-survival role in renal epithelia under moderate oxidative stress. We and others have demonstrated that during severe oxidative stress, however, the activated EGFR is disconnected from ERK activation in cultured renal proximal tubule cells and also in renal proximal tubules after ischemia/reperfusion injury, resulting in necrotic death. Studies have shown that the tyrosine-phosphorylated p46/52 isoforms of the ShcA family of adaptor proteins connect the activated EGFR to activation of Ras and ERK, whereas the p66(shc) isoform can inhibit this p46/52(shc) function.

Restoration of CREB function ameliorates cisplatin cytotoxicity in renal tubular cells.

We have shown that mouse proximal tubule cells (TKPTS) survive H(2)O(2) stress by activating the cAMP-responsive element binding protein (CREB)-mediated transcription via the canonical EGFR-Ras/ERK pathway. By contrast, cisplatin activates EGFR/Ras/ERK signaling in TKPTS cells yet promotes cell death rather than survival. We now demonstrate that the cisplatin-induced activated EGFR/Ras/ERK signaling cascade fails to activate CREB-mediated transcription even in the presence of phosphorylated CREB.

Involvement of the CDK2-E2F1 pathway in cisplatin cytotoxicity in vitro and in vivo.

E2F1 is a key regulator that links cell cycle progression and cell death. E2F1 activity is controlled by Cdk2-cyclin complexes via several mechanisms, such as phosphorylation of retinoblastoma protein (pRb) to release E2F1, direct phosphorylation, and stable physical interaction. We have demonstrated that cisplatin cytotoxicity depends on Cdk2 activity, and Cdk2 inhibition protects kidney cells from cisplatin-induced cell death in vitro and in vivo.

Dependence of cisplatin-induced cell death in vitro and in vivo on cyclin-dependent kinase 2.

Cisplatin is one of the most effective chemotherapeutics, but its usefulness is limited by its toxicity to normal tissues, including cells of the kidney proximal tubule. The purpose of these studies was to determine the mechanism of cisplatin cytotoxicity. It was shown in vivo that cisplatin administration induces upregulation of the gene for the p21 cyclin-dependent kinase (cdk) inhibitor in kidney cells.

CREB mediates ERK-induced survival of mouse renal tubular cells after oxidant stress.

Background: We showed that extracellular signal-regulated protein kinase (ERK) is prosurvival during oxidant stress both in the kidney and in cultured mouse proximal tubule (TKPTS) cells and demonstrated concomitant activation of ERK as well as the cyclic adenosine monophosphate (cAMP)-responsive element binding protein (CREB), during survival in vitro. We now show that CREB is a necessary prosurvival target of ERK.

Methods: Ischemia/reperfusion (I/R) injury was induced in 129Sv mice.

Identification of the functional domain of p21(WAF1/CIP1) that protects cells from cisplatin cytotoxicity.

The p21 cyclin-dependent kinase (cdk) inhibitor protects cells from cisplatin cytotoxicity in vivo and in vitro. However, the mechanism of protection is not known. Separate p21 domains are known to interact with several different proteins having proapoptotic functions.

Acute renal failure: from renal physiology to the renal transcriptome.

Acute renal failure (ARF) is defined as an abrupt fall in glomerular filtration rate. Fully 5% of all patients admitted to the hospital undergo ARF with an attendant increase in morbidity and mortality. We have studied murine models of ischemia/reperfusion and cisplatin-induced renal failure in detail to determine the physiologic and molecular events that are responsible for the syndrome.

Cisplatin-induced cell death is EGFR/src/ERK signaling dependent in mouse proximal tubule cells.

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.

Activation of ERK or inhibition of JNK ameliorates H(2)O(2) cytotoxicity in mouse renal proximal tubule cells.

Background: Our previous studies suggest that the balance between the activation of extracellular signal-regulated kinase (ERK) and the c-Jun N-terminal/stress-activated protein kinase (JNK) might determine cell fate following oxidant injury in vivo.

Methods: The mouse proximal tubule cell line (TKPTS) was used to study hydrogen peroxide (H(2)O(2))-induced death and survival. The role of ERK and JNK in this process was studied by using adenoviruses that contain either a constitutively active mitogen-activated protein kinase kinase 1 (MEK1) or a dominant-negative JNK.

Cisplatin nephrotoxicity.

Cisplatin remains a major antineoplastic drug for the treatment of solid tumors. Its chief dose-limiting side effect is nephrotoxicity, which evolves slowly and predictably after initial and repeated exposure. The kidney accumulates cisplatin to a higher degree than other organs perhaps via mediated transport.

Cell cycle regulation: repair and regeneration in acute renal failure.

Research into mechanisms of acute renal failure has begun to reveal molecular targets for possible therapeutic intervention. Much useful knowledge into the causes and prevention of this syndrome has been gained by the study of animal models. Most recently, investigation of the effects on acute renal failure of selected gene knock-outs in mice has contributed to our recognition of many previously unappreciated molecular pathways.

Protection of renal cells from cisplatin toxicity by cell cycle inhibitors.

The optimal use of cisplatin as a chemotherapeutic drug has been limited by its nephrotoxicity. Murine models have been used to study cisplatin-induced acute renal failure. After cisplatin administration, cells of the S3 segment in the renal proximal tubule are especially sensitive and undergo extensive necrosis in vivo.

Monocyte chemoattractant protein-1 expression correlates with monocyte infiltration in the post-ischemic kidney.

Chemokines play a prominent role in the acute inflammatory response in several models of kidney disease. We reported that monocyte chemotactic peptide-1 (MCP-1) mRNA is increased by ischemia-reperfusion injury. In this report, we examined the effects of ischemia-reperfusion injury on the kinetics and location of MCP-1 protein expression, the excretion of MCP- 1 protein in the urine and on the infiltration of mononuclear cells in the kidney.

Coordination of the cell cycle is an important determinant of the syndrome of acute renal failure.

Recovery from injury is usually accompanied by cell replication, in which new cells replace those irreparably damaged. After acute renal failure, normally quiescent kidney cells enter the cell cycle, which in tubule segments is accompanied by the induction of cell cycle inhibitors. We found that after acute renal failure induced by either cisplatin injection or renal ischemia, induction of the p21 cyclin-dependent kinase (cdk) inhibitor is protective.