Cisplatin nephrotoxicity and protection by milk thistle extract in rats

The protective effect of methanolic extract of milk thistle seeds and silymarin against cisplatin-induced renal toxicity in male rats after a single intraperitoneal injection of 3 mg kg cisplatin were studied. Over 5 days, cisplatin-treated rats showed tubular necrosis and elevation in blood urea nitrogen (BUN) and serum creatinine (Scr). Pretreatment of animals with silymarin (50 mg kg) or extract (0.6 g kg) 2 h before cisplatin prevented the tubular damage. Rats treated with silymarin or extract 2 h after cisplatin had BUN and Scr significantly lower than those receiving cisplatin, but mild to moderate necrosis was observed. These results suggested that milk thistle may protect against cisplatin-induced renal toxicity and might serve as a novel combination agent with cisplatin to limit renal injury.     

A novel free radical scavenger,edarabone, protects against cisplatin-induced acute renal damage in vitro and in vivo

Accumulating evidence suggests that enhanced peroxidative damage caused by reactive oxygen species (ROS) may contribute to the pathogenesis of cisplatin-induced acute renal failure. Nevertheless, little is known about the involvement of oxygen radicals in cisplatin nephropathy. In this study, we investigated the effects of a novel free radical scavenger, 3-methyl-1-phenyl-pyrazolin-5-one (MCI-186; edarabone), on murine proximal tubular cell (PTC) damage induced by exposure to cisplatin in vitro and on renal function in an in vivo model of cisplatin-induced acute renal failure. Edarabone inhibited cisplatin-induced (40 microM, 24 h) cytotoxicity in a concentration-dependent manner (10-5 to 10-3 M). Edarabone also attenuated cisplatin-induced mitochondrial transmembrane potential loss and ROS production of PTCs. In the in vivo study, male Wistar rats were cotreated with cisplatin (5 mg/kg, i.p.) and edarabone (1 or 5 mg/kg, i.v.). Effects of edarabone on the kidney were examined 5 days after treatment. Cisplatin resulted in renal dysfunction, renal tubular damage, mitochondrial damage (assayed by histochemical staining for respiratory chain complex IV), renal protein oxidation (examined by Western blot analysis using a specific antibody for carbonyl group-containing proteins), and tubular apoptosis (determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining). The above changes were attenuated by edarabone treatment. Thus, edarabone exhibited cytoprotective effects in PTCs and renoprotective effects against cisplatin. Our findings suggest that ROS, in particular hydroxyl radicals, are involved in cisplatin nephropathy and that edarabone may be potentially useful in protecting the kidneys and prevention of acute renal failure.     

Erythropoietin in experimental acute renal failure

The haematopoietic factor erythropoietin (EPO) has recently been recognized to play a physiological role in the brain and other tissues. The EPO receptor is present in the glomerulus, mesangial and tubular epithelial cells in the kidney. We have reviewed the experimental use of EPO in animal models of acute renal failure. EPO attenuates the dysfunction and histological changes associated with ischaemia-reperfusion injury, with a reduction in apoptotic cell death. EPO has also shown benefit in animal models of systemic shock and cisplatin-induced nephrotoxicity. In vitro studies have shown that EPO has direct effects on proliferation and cell death in proximal tubular epithelial cells. There is increasingly strong experimental evidence that EPO may be of therapeutic use in acute renal failure, and clinical trials should be undertaken to determine its clinical applications in this field.     

Attenuation of cisplatin-induced acute renal failure is associated with less apoptotic cell death

To clarify the pathophysiologic role of apoptosis in acute renal failure (ARF), we examined whether the attenuation of cisplatin-induced ARF is associated with the change in the degree of apoptotic cell death. The administration of cisplatin (CDDP) (6 mg/kg body weight) in rats induced ARF at day 5, as manifested by a significant increase in serum creatinine (Scr) and tubular damage. CDDP-induced apoptotic cell death was confirmed by electron microscopic examination, agarose gel electrophoresis, and increased cells positive for TaT-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) in the outer medulla of the kidney. Treatment with dimethylthiourea (DMTU)--a scavenger of hydroxyl radicals--or glycine abrogated CDDP-induced increases in Scr, the tubular damage score, and the number of TUNEL-positive cells. Pretreatment with uranyl acetate (UA) induced a significant expression of Bcl-2 in the kidney and ameliorated CDDP-induced increases in Scr, the tubular damage score, and TUNEL-positive cells in the outer stripe of the outer medulla. Our findings indicate (1) that the attenuation of CDDP-induced ARF was associated with less apoptotic cell death and (2) that the induction of the anti-apoptotic protein Bcl-2 attenuated apoptosis and tubular damage. Our results suggest that apoptotic cell death may play an important role in the development of cisplatin-induced ARF.     

Serum transferrin receptor is a marker of iron deficiency in patients included in programs for preoperative autologous blood donation.

Recently programs for preoperative autologous blood donation (PABD) have expanded to reduce the need for allogenic blood transfusion. Nevertheless, the ability of the patients's bone marrow to replace the red blood cells (RBCs) mass reduced by phlebotomies determines the efficacy of PABD. In mild anemia, known as iron-deficient erythropoiesis (IDE) or iron deficiency without anemia, precipitated by PABD, the marrow response is suboptimal and needs adjuvant therapy. The aim of this study was to evaluate the use of the serum transferrin receptor (sTfR) for the assessment of IDE in patients undergoing PABD. METHODS: Two autologous blood units from 50 consecutive patients scheduled for elective orthopedic surgery were collected preoperatively. Serial measurements of RBCs, haematocrit (Hct), haemoglobin (Hb), serum iron, serum ferritin, reticulocyte count, reticulocyte maturity index (RMI), endogenous erythropoietin (EPO) and sTfR were performed throughout the phlebotomy program. RESULTS: RBC, Hct, Hb and serum iron significantly decreased although within the normal range. There was no change in serum ferritin levels. Reticulocytes, RMI and EPO significantly increased as did sTfR which significantly exceeds the normal range. CONCLUSIONS: These results demonstrate that the sTfR is a reliable laboratory marker for detecting mild anemia or IDE. In patients undergoing PABD increased sTfR levels may suggest a treatment with recombinant human EPO (rh-EPO) or iron to improve the bone marrow performance.     

TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity

The purpose of these studies was to examine the role of cytokines in the pathogenesis of cisplatin nephrotoxicity. Injection of mice with cisplatin (20 mg/kg) led to severe renal failure. The expression of cytokines, chemokines, and ICAM-1 in kidney was measured by ribonuclease protection assays and RT-PCR. We found significant upregulation of TNF-alpha, TGF-beta, RANTES, MIP-2, MCP-1, TCA3, IL-1beta, and ICAM-1 in kidneys from cisplatin-treated animals. In addition, serum, kidney, and urine levels of TNF-alpha measured by ELISA were increased by cisplatin. Inhibitors of TNF-alpha production (GM6001, pentoxifylline) and TNF-alpha Ab's reduced serum and kidney TNF-alpha protein levels and also blunted the cisplatin-induced increases in TNF-alpha, TGF-beta, RANTES, MIP-2, MCP-1, and IL-1beta, but not ICAM-1, mRNA. In addition, the TNF-alpha inhibitors also ameliorated cisplatin-induced renal dysfunction and reduced cisplatin-induced structural damage. Likewise, TNF-alpha-deficient mice were resistant to cisplatin nephrotoxicity. These results indicate cisplatin nephrotoxicity is characterized by activation of proinflammatory cytokines and chemokines. TNF-alpha appears to play a central role in the activation of this cytokine response and also in the pathogenesis of cisplatin renal injury.     

红细胞生成素治疗前后肾性贫血患儿网织红细胞参数变化情况及临床意义

目的探讨红细胞生成素（EPO）治疗前后肾性贫血患儿网织红细胞参数变化情况及临床意义。方法采用Beckman coulter LH750全自动血液分析仪及Beckman LX20全自动生化分析仪,检测EPO治疗前65例慢性肾功能不全不同病期患儿和65名正常对照的红细胞（RBC）计数、血红蛋白（Hb）含量、网织红细胞百分比（Ret％）、网织红细胞不成熟度（IRF）和平均网织红细胞体积（MRV）,同时检测其血清肌酐（Cr）和尿素氮（BUN）含量,并进行比较分析;比较EPO治疗前、后肾性贫血患儿Ret％、RBC、Hb、IRF、MRV等参数的变化。结果EPO治疗前,氮质血症组和肾功能衰竭组的Ret％较对照组均有升高,但IRF值基本正常或略低;经过EPO治疗后肾功能不全患儿的贫血状态明显得到改善,IRF值和MRV值明显升高,IRF值升高的程度比Ret％更加明显。结论Ret参数尤其是IRF值的检测,有助于了解肾性贫血患儿的骨髓增生程度和红系的生长情况。     

促红细胞生成素防治大鼠急性肾小管坏死的实验研究

目的 探讨促红细胞生成素对大鼠急性肾小管坏死的防治作用.方法 按10 mL·kg-1肌肉注射甘油建立大鼠急性肾小管坏死模型.30只Wistar大鼠随机(随机数字法)分为正常组、模型组、治疗组.治疗组予促红细胞生成素(1000 IU·kg-1)尾静脉注射,实验结束时检测各组大鼠血尿素氮(Bun)、血肌酐(Scr)、尿渗量、尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG)、尿β2微球蛋白(β2-MG),肾组织匀浆丙二醇(MDA)和超氧化物歧化酶(SOD),并进行肾脏组织学观察.结果 与模型组比较,治疗组大鼠Bun、Scr、尿NAG、尿β2-MG、肾组织匀浆MDA明显下降,而尿渗量、肾组织匀浆SOD升高,肾脏病理改变好转.结论 促红细胞生成素可能通过抗氧自由基损伤,提高内源性抗氧化能力达到对急性肾小管坏死大鼠肾脏的部分保护作用.     

Increased plasma viscosity as a reason for inappropriate erythropoietin formation.

The aim of this study was to examine whether altered plasma viscosity could contribute to the inappropriately low production rate of erythropoietin (EPO) observed in patients suffering from hypergammaglobulinemias associated with multiple myeloma or Waldenström's disease. We found that the EPO formation in response to anemia in these patients was inversely related to plasma viscosity. A similar inverse relationship between plasma viscosity and EPO production was seen in rats in which EPO formation had been stimulated by exchange transfusion and the plasma viscosity of which was thereby altered by using exchange solutions of different composition to alter plasma viscosity and thus whole blood viscosity independently from hematocrit. Raising the gammaglobulin concentration to approximately 40 mg/ml plasma in the rats almost totally blunted the rise in serum EPO levels despite a fall of the hematocrit to 20%. Determination of renal EPO mRNA levels by RNase protection revealed that the reductions in serum EPO levels at higher plasma viscosities were paralleled by reductions in renal EPO mRNA levels. Taken together, our findings suggest that plasma viscosity may be a significant inhibitory modulator of anemia-induced EPO formation. The increased plasma viscosity in patients with hypergammaglobulinemias may therefore contribute to the inappropriate EPO production, which is a major reason for the anemia developing in these patients.     

红细胞生成素治疗前后肾性贫血患儿网织红细胞参数变化情况及临床意义

目的探讨红细胞生成素(EPO)治疗前后肾性贫血患儿网织红细胞参数变化情况及临床意义。方法采用Beckm an cou lter LH 750全自动血液分析仪及Beckm an LX20全自动生化分析仪,检测EPO治疗前65例慢性肾功能不全不同病期患儿和65名正常对照的红细胞(RBC)计数、血红蛋白(Hb)含量、网织红细胞百分比(Ret%)、网织红细胞不成熟度(IRF)和平均网织红细胞体积(MRV),同时检测其血清肌酐(Cr)和尿素氮(BUN)含量,并进行比较分析;比较EPO治疗前、后肾性贫血患儿Ret%、RBC、Hb、IRF、MRV等参数的变化。结果EPO治疗前,氮质血症组和肾功能衰竭组的Ret%较对照组均有升高,但IRF值基本正常或略低;经过EPO治疗后肾功能不全患儿的贫血状态明显得到改善,IRF值和MRV值明显升高,IRF值升高的程度比Ret%更加明显。结论Ret参数尤其是IRF值的检测,有助于了解肾性贫血患儿的骨髓增生程度和红系的生长情况。     

肾性贫血患者网织红细胞参数的变化及临床意义

目的探讨网织红细胞参数在肾性贫血治疗中的变化及临床意义。方法采用Sysmex XE-2100型自动血液分析仪,检测88例各种肾病(包括45例用抗贫血药治疗组和43例未用抗贫血药治疗组)和80例正常对照组的网织红细胞百分率(Ret%)、网织红细胞绝对值(Ret#)、未成熟网织红细胞比率(IRF%)、低荧光网织红细胞比率(LFR%)、中荧光网织红细胞比率(MFR%)、高荧光网织红细胞比率(HFR%),并进行比较分析。结果治疗组的Ret%、Ret#、IRF%、MFR%、HFR%均显著高于未治疗组(P<0.01)。未治疗组的Ret%、IRF%和MFR%均显著低于对照组(P<0.01)。治疗组的Ret%、IRF%、MFR%、HFR%均显著高于对照组(P<0.01)。以Ret%>1.73%和IRF%>8.99%为界线,评价本组抗贫血治疗效果的特异性为86.1%和97.7%,敏感性为62.2%和53.3%,阳性预测值为82.4%和96.0%,阴性预测值为68.5%和66.7%。结论网织红细胞参数的检测有助于了解肾病患者骨髓增生程度和红系的生长情况;IRF在肾病早期降低,经促红细胞生成素(EPO)等抗贫血药治疗后IRF升高,提示EPO等治疗有效。     

Ratio of baseline erythropoietin (EPO) level and corrected reticulocyte count as an indicator for a favourable response to recombinant human erythropoietin (rhEPO) therapy in anaemic cancer patients

PURPOSE: Recently, recombinant human erythropoietin (rhEPO) was introduced for the management of anemia in malignancy. To identify an indicator for a favourable response to rhEPO, 28 anaemic cancer patients undergoing chemotherapy and treated with rhEPO were evaluated. METHODS: Patients were classified into responder (16 of 28, 57%) and nonresponder (12 of 28, 43%) groups according to their responses to rhEPO therapy (response being defined as an increase in Hb level of > 2 g/dl from baseline without blood transfusion). RESULTS: Treatment with rhEPO showed significant improvements in the red blood cell (RBC) count, haemoglobin (Hb), packed cell volume (PCV), and reticulocyte count (ret. count) after 4 weeks. Upon analysing the baseline value of the EPO level and the corrected ret.count in these two groups, we found that the ratio of the EPO level and the corrected ret.count (EPO/ret.count) demonstrated a statistical significance (P = 0.03) in the prediction of response to rhEPO therapy. This ratio showed a sensitivity of 87.5%, specificity of 66.7%, and overall accuracy of 78.6%. CONCLUSION: Our study suggested that the baseline ratio of EPO/ret.count should be used as an indicator for a favourable response to rhEPO therapy.     

Cisplatin-induced renal cell apoptosis: caspase 3-dependent and -independent pathways

The chemotherapeutic cisplatin causes renal dysfunction and renal proximal tubular cell (RPTC) apoptosis. The goal of these studies was to examine the role of p53, caspase 3, 8, and 9, and mitochondria in the signaling of cisplatin-induced apoptosis. Cisplatin (50 microM) produced time-dependent apoptosis in RPTCs, causing cell shrinkage, a 50-fold increase in caspase 3 activity, a 4-fold increase in phosphatidylserine externalization, and 5- and 15-fold increases in chromatin condensation and DNA hypoploidy, respectively. Mitochondrial membrane potential and ATP levels did not change at any time during cisplatin exposure. Caspase 8 and 9 activities also did not increase during treatment. Cisplatin increased nuclear p53 expression 4 h after treatment, preceding both caspase 3 activation and chromatin condensation. Treatment with the p53 inhibitor alpha-2-(2-imino-4,5,6,7-tetrahydrobenzothiazol-3-yl)-1-p-tolylethanone (PFT) before cisplatin exposure inhibited p53 nuclear expression at 4, 8, and 12 h and inhibited phosphatidylserine externalization and caspase 3 activation at 12 h. Neither DEVD-fmk nor ZVAD-fmk inhibited cisplatin-induced p53 nuclear expression. Both DEVD-fmk and ZVAD-fmk completely inhibited caspase 3 activity but, like PFT, partially inhibited cisplatin-induced chromatin condensation, annexin V labeling, and DNA hypoploidy after 24 h. These data demonstrate that at least 50% of cisplatin-induced apoptosis in RPTC is mediated by p53 and that p53 activates caspase 3 independently of either caspase 9 or 8 or mitochondrial dysfunction. Furthermore, 50% of cisplatin-induced RPTC apoptosis is independent of p53 and caspases 3, 8, and 9.     

Inhibition of PKCδ reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer

Cisplatin is a widely used cancer therapy drug that unfortunately has major side effects in normal tissues, notably nephrotoxicity in kidneys. Despite intensive research, the mechanism of cisplatin-induced nephrotoxicity remains unclear, and renoprotective approaches during cisplatin-based chemotherapy are lacking. Here we have identified PKCδ as a critical regulator of cisplatin nephrotoxicity, which can be effectively targeted for renoprotection during chemotherapy. We showed that early during cisplatin nephrotoxicity, Src interacted with, phosphorylated, and activated PKCδ in mouse kidney lysates. After activation, PKCδ regulated MAPKs, but not p53, to induce renal cell apoptosis. Thus, inhibition of PKCδ pharmacologically or genetically attenuated kidney cell apoptosis and tissue damage, preserving renal function during cisplatin treatment. Conversely, inhibition of PKCδ enhanced cisplatin-induced cell death in multiple cancer cell lines and, remarkably, enhanced the chemotherapeutic effects of cisplatin in several xenograft and syngeneic mouse tumor models while protecting kidneys from nephrotoxicity. Together these results demonstrate a role of PKCδ in cisplatin nephrotoxicity and support targeting PKCδ as an effective strategy for renoprotection during cisplatin-based cancer therapy.     

Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models

The mechanism of mitochondrial damage, a key contributor to renal tubular cell death during acute kidney injury, remains largely unknown. Here, we have demonstrated a striking morphological change of mitochondria in experimental models of renal ischemia/reperfusion and cisplatin-induced nephrotoxicity. This change contributed to mitochondrial outer membrane permeabilization, release of apoptogenic factors, and consequent apoptosis. Following either ATP depletion or cisplatin treatment of rat renal tubular cells, mitochondrial fragmentation was observed prior to cytochrome c release and apoptosis. This mitochondrial fragmentation was inhibited by Bcl2 but not by caspase inhibitors. Dynamin-related protein 1 (Drp1), a critical mitochondrial fission protein, translocated to mitochondria early during tubular cell injury, and both siRNA knockdown of Drp1 and expression of a dominant-negative Drp1 attenuated mitochondrial fragmentation, cytochrome c release, caspase activation, and apoptosis. Further in vivo analysis revealed that mitochondrial fragmentation also occurred in proximal tubular cells in mice during renal ischemia/reperfusion and cisplatin-induced nephrotoxicity. Notably, both tubular cell apoptosis and acute kidney injury were attenuated by mdivi-1, a newly identified pharmacological inhibitor of Drp1. This study demonstrates a rapid regulation of mitochondrial dynamics during acute kidney injury and identifies mitochondrial fragmentation as what we believe to be a novel mechanism contributing to mitochondrial damage and apoptosis in vivo in mouse models of disease.     

Prevention and management of nephrotoxicity from anti-cancer agents

Nephrotoxicity is an inherent adverse effect of certain anticancer drugs. Mechanisms of chemotherapy-induced renal dysfunction generally include damage to vascular or structures of the kidneys, hemolytic uremic syndrome and prerenal perfusion deficits. Patients with cancer are frequently at risk of renal impairment secondary to disease-related and iatrogenic causes. This article reviews the prevention and management of anticancer drug-induced renal dysfunction. Cisplatin and carboplatin cause dose-related renal dysfunction. In addition to elevation of serum creatinine levels and uremia, electrolyte abnormalities, such as hypomagnesemia and hypokalemia, are well known adverse effects of cisplatin. Methotrexate can cause elevation of serum creatinine levels, uremia and hematuria. Acute renal failure is reported after high dose methotrexate therapy. Urinary alkalization and hydration confer protection against methotrexate-induced renal dysfunction. Dose- and age-related proximal tubular damage is an adverse effect of ifosfamide. In addition to renal wasting of electrolytes, glucose and amino acids, Fanconi syndrome and rickets after ifosfamide administration have been reported in the literature. Hemolytic uremia is a rare but serious adverse effect of gemcitabine.     

Anemia with erythropoietin deficiency occurs early in diabetic nephropathy

OBJECTIVE: The normochromic normocytic anemia of erythropoietin (EPO) deficiency is recognized in advanced renal failure but not in early renal disease. The aim of this study was to determine whether anemia with EPO deficiency is found in type 1 diabetic patients with diabetic nephropathy in the absence of advanced renal failure and to compare them with patients with nondiabetic renal disease of similar severity. RESEARCH DESIGN AND METHODS: A total of 27 type 1 diabetic patients with diabetic nephropathy (DN), defined as having persistent proteinuria (mean 1,086 mg/day [CI 120-5,1901), a serum creatinine < or = 180 micromol/l, and retinopathy, were compared with 26 nondiabetic patients with glomerulonephritis (GN) and persistent proteinuria (1,874 mg/day [349-5,005]). The Hb concentration, red cell indexes, and serum EPO levels were measured, and other causes for the anemia were excluded. The EPO values were compared with a normal reference range obtained from nondiabetic patients with a microcytic anemia. The DN patients were tested for signs of diabetic peripheral and autonomic neuropathy. RESULTS: We found that 13 of the 27 DN patients were anemic (Hb 10.6 +/- 0.9 g/dl) in marked contrast to none of the GN patients (Hb 13.7 +/- 1.4 g/dl, P < 0.005). In the DN group, serum EPO concentrations failed to increase in response to anemia compared with the response seen in patients with microcytic anemia. Thus, the anemia of the DN group was associated with EPO deficiency. The anemic DN patients showed evidence of more severe proteinuria and diabetic neuropathy than the nonanemic DN patients. CONCLUSIONS: Anemia associated with EPO deficiency can occur early in DN before the onset of advanced renal failure, but does not normally occur in nondiabetic renal disease of similar severity. The pathogenesis requires elucidation.     

Coulter LH 750仪网织红细胞检测参数的临床价值分析

目的探讨BeckmanCoulterLH750全自动血液分析仪检测网织红细胞及其新型参数的方法及临床应用价值。方法用BeckmanCoulterLH750全自动血液分析仪检测248例住院贫血患者抗凝全血标本的网织红细胞百分比(RET％)、网织红细胞绝对值(RET#)、网织红细胞平均体积(MRV)、未成熟网织红细胞组分(IRF)、高散射光强度网织红细胞百分比(HLR％)等五项网织红细胞参数。结果慢性肾功能不全的贫血患者RET#同对照组比较无显著差异,但HLR％显著高于对照组(P<0.05)。失血性贫血的患者网织红细胞各项指标与对照组相比显著增高;肝硬化与正常对照组RET％、RET#和HLR％有显著差异(P<0.05)。结论测定网织红细胞及其相关参数有助于判断红细胞的活动度,对贫血类型的初筛诊断、治疗监测等有重要的实用价值。     

Attenuation of cisplatin-induced renal injury by inhibition of soluble epoxide hydrolase involves nuclear factor κB signaling

Acute kidney injury is associated with a significant inflammatory response that has been the target of renoprotection strategies. Epoxyeicosatrienoic acids (EETs) are anti-inflammatory cytochrome P450-derived eicosanoids that are abundantly produced in the kidney and metabolized by soluble epoxide hydrolase (sEH; Ephx2) to less active dihydroxyeicosatrienoic acids. Genetic disruption of Ephx2 and chemical inhibition of sEH were used to test whether the anti-inflammatory effects of EETs, and other lipid epoxide substrates of sEH, afford protection against cisplatin-induced nephrotoxicity. EET hydrolysis was significantly reduced in Ephx2(-/-) mice and was associated with an attenuation of cisplatin-induced increases in serum urea nitrogen and creatinine levels. Histological evidence of renal tubular damage and neutrophil infiltration was also reduced in the Ephx2(-/-) mice. Likewise, cisplatin had no effect on renal function, neutrophil infiltration, or tubular structure and integrity in mice treated with the potent sEH inhibitor 1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea) (AR9273). Consistent with the ability of EETs to interfere with nuclear factor-κB (NF-κB) signaling, the observed renoprotection was associated with attenuation of renal NF-κB activity and corresponding decreases in the expression of tumor necrosis factor (TNF) α, TNF receptor (TNFR) 1, TNFR2, and intercellular adhesive molecule-1 before the detection of tubular injury. These data suggest that EETs or other fatty acid epoxides can attenuate cisplatin-induced kidney injury and sEH inhibition is a novel renoprotective strategy.     

Sirtuin 3–dependent mitochondrial dynamic improvements protect against acute kidney injury

Acute kidney injury (AKI) is a public health concern with an annual mortality rate that exceeds those of breast and prostate cancer, heart failure, and diabetes combined. Oxidative stress and mitochondrial damage are drivers of AKI-associated pathology; however, the pathways that mediate these events are poorly defined. Here, using a murine cisplatin-induced AKI model, we determined that both oxidative stress and mitochondrial damage are associated with reduced levels of renal sirtuin 3 (SIRT3). Treatment with the AMPK agonist AICAR or the antioxidant agent acetyl-l-carnitine (ALCAR) restored SIRT3 expression and activity, improved renal function, and decreased tubular injury in WT animals, but had no effect in Sirt3^–/– mice. Moreover, Sirt3-deficient mice given cisplatin experienced more severe AKI than WT animals and died, and neither AICAR nor ALCAR treatment prevented death in Sirt3^–/– AKI mice. In cultured human tubular cells, cisplatin reduced SIRT3, resulting in mitochondrial fragmentation, while restoration of SIRT3 with AICAR and ALCAR improved cisplatin-induced mitochondrial dysfunction. Together, our results indicate that SIRT3 is protective against AKI and suggest that enhancing SIRT3 to improve mitochondrial dynamics has potential as a strategy for improving outcomes of renal injury.