Abstract:
BACKGROUND:Cellular and molecular mechanisms responsible for cisplatin-induced nephrotoxicity to renal tubular epithelial cells are not well understood. Although caspases play a critical role in the execution of the cell death pathway, their specific role in toxic injury to renal tubular epithelial cells has not been elucidated previously. METHODS:The role of caspases in cisplatin-induced injury was determined using caspase inhibitors and p35 transfected LLC-PK1 cells. The Akt/PKB phosphorylation pathway was studied for the regulation of caspase activation in these cells. RESULTS:The activation of initiator caspases-8, -9 and -2, and executioner caspase-3 began after eight hours of cisplatin treatment, thereafter markedly increased in a time (8 to 24 hours) and dose-dependent manner (0 to 200 micromol/L). Proinflammatory caspase-1 did not show cisplatin-induced activation. Inhibition of caspase-3 by over expressing cowpox virus p35 protein or alternatively by the peptide inhibitor DEVD-CHO provided marked protection against cell death and partial protection against DNA damage. We then examined the role of the Akt/PKB phosphorylation pathway in regulation of cisplatin-induced caspase activation. There was a marked induction of Akt/PKB phosphorylation in a time (0 to 8 hours) and dose-dependent (0 to 200 micromol/L) manner during the course of cisplatin injury. Cisplatin-induced Akt/PKB activation was associated with Bad phosphorylation, suggesting induction of a cell survival signal mediated by the Bcl-2 family member, Bad. Wortmannin or LY294002, two structurally dissimilar inhibitors of phosphatidylinositol 3'-kinase (PI-3 kinase), abolished both cisplatin-induced Akt phosphorylation and Bad phosphorylation, and promoted cisplatin-induced early and accelerated activation of caspase-3 and caspase-9, but not of caspase-8 and caspase-1, indicating that inhibition of the Akt/PKB phosphorylation pathway enhances the mitochondrial-dependent activation of caspases. The impact of enhanced activation of caspases by wortmannin or LY294002 was reflected on accelerated cisplatin-induced cell death. CONCLUSIONS:These studies demonstrate differential activation and role of caspases in cisplatin injury, and provide the first evidence of cisplatin-induced induction of the Akt/PKB phosphorylation pathway, inhibition of which enhances activation of caspase-3 and caspase-9.
journal_name
Kidney Intjournal_title
Kidney internationalauthors
Kaushal GP,Kaushal V,Hong X,Shah SVdoi
10.1046/j.1523-1755.2001.00026.xsubject
Has Abstractpub_date
2001-11-01 00:00:00pages
1726-36issue
5eissn
0085-2538issn
1523-1755pii
S0085-2538(15)48053-6journal_volume
60pub_type
杂志文章abstract::We examined the effect of daily cyclosporin A administration on the development and extent of tubulointerstitial nephritis produced in rats immunized with tubular basement membranes in adjuvant. Six mg/kg/day of cyclosporin A, given from the time of immunization, completely blocked the development of interstitial lesi...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1988.119
更新日期:1988-06-01 00:00:00
abstract::Long-term treatment (8 and 13 weeks) of rats with FGF-2 led to albuminuria and to increase in serum creatinine indicating the development of chronic renal failure. Histologically, the classic picture of focal segmental glomerulosclerosis (FSGS) was found; males were more severely affected than females. Among the early...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1995.433
更新日期:1995-11-01 00:00:00
abstract::The maximum rate of inorganic phosphorus (P1) reabsorption (Tmp1) was measured during phosphate infusion in chronically parathyroidectomized rats. In either initially hydropenic rats or others which underwent moderate preliminary saline loading, Tmp1 tended to rise during early phosphate infusion and then decline, so ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1975.85
更新日期:1975-08-01 00:00:00
abstract::Many transgenic and knockout mice with increased urine flow have structural abnormalities of the renal pelvis and inner medulla. Here, we used high resolution contrast enhanced T1-weighted magnetic resonance imaging of mice whose urea transporters UT-A1 and UT-A3 were deleted (UT-A1/3(-/-) mice) as a model for the in ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2008.392
更新日期:2008-11-01 00:00:00
abstract::It has been shown that somatostatin inhibits the antidiuretic action of vasopressin in toad urinary bladder in vitro and in dogs and rats in vivo. The presence of somatostatin-like immunoreactivity (SLI) in the urinary bladder and kidney of the toad has suggested the possibility that somatostatin may act as a local pa...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1983.223
更新日期:1983-12-01 00:00:00
abstract::We used the perfused hemicorpus preparation to measure individual rates of protein synthesis and degradation. Using fed animals, perfused either with or without insulin, muscle protein synthesis and hemicorpus protein degradation rates were similar, but myofibrillar protein degradation was clearly increased in the ure...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1986.119
更新日期:1986-06-01 00:00:00
abstract:BACKGROUND:The peritoneum is progressively denuded of its mesothelial cell monolayer in patients on continuous ambulatory peritoneal dialysis (CAPD). These alterations of the mesothelium cause membrane dysfunction and progressive peritoneal fibrosis. Integrins regulate cell motility and play an important role in wound ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2003.00772.x
更新日期:2003-02-01 00:00:00
abstract::The antiphospholipid syndrome is a common autoimmune disease caused by pathogenic antiphospholipid antibodies, leading to recurrent thrombosis and/or obstetrical complications. Importantly for nephrologists, antiphospholipid antibodies are associated with various renal manifestations including large renal vessel throm...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1016/j.kint.2016.06.026
更新日期:2017-01-01 00:00:00
abstract::Human mesangial cells (MC) in culture, when stimulated by interleukin 1 alpha(IL-1 alpha) or tumour necrosis factor (TNF alpha), but not with lipopolysaccharide (LPS), express interleukin 8 (IL-8) mRNA, and both cell associated and extracellular IL-8. Dexamethasone treatment of mesangial cells induced partial inhibiti...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1991.184
更新日期:1991-07-01 00:00:00
abstract::Intravenous conjugated estrogens reduce the prolonged bleeding time in uremic patients and in a rat model of uremia. However, estrogens have major side effects related to their hormonal activity. We investigated whether a beta-resorcylic acid lactone, zeranol (a compound with close spatial similarity to estrogens but ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1990.172
更新日期:1990-07-01 00:00:00
abstract::Measures related to red cell oxygen transport were evaluated in 17 hemodialysis patients receiving androgen therapy, 15 untreated hemodialysis patients and 15 normal subjects. Hemoglobin levels were higher in androgen-treated patients than in the untreated population and were directly related to the reticulocyte index...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1987.15
更新日期:1987-01-01 00:00:00
abstract::Isolated perfused rat kidneys were passively sensitized by addition of either mouse ascitic fluid containing monoclonal IgE against dinitrophenol (DNP) or DNP-specific purified IgE. After washing the organ, defined doses of DNP-bovine serum albumin were given as bolus injection via the kidney artery. Antigen challenge...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1987.197
更新日期:1987-08-01 00:00:00
abstract::The effects of chronic respiratory alkalosis on divalent ion homeostasis have not been reported in any species. We studied four normal male subjects during a four-day control period (residence at 500 m), during six days of chronic respiratory alkalosis induced by hypobaric hypoxia (residence at 3450 m), followed by a ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1992.340
更新日期:1992-09-01 00:00:00
abstract::The Executive Summary of the KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients is presented in this issue of Kidney International. This guideline will require careful attention for implementation in the context of available resources within each country, especially those with underdevelope...
journal_title:Kidney international
pub_type: 评论,杂志文章
doi:10.1038/ki.2009.468
更新日期:2010-02-01 00:00:00
abstract:BACKGROUND:Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF-A) is expressed constitutively in the adult glomerular podocytes at high levels; however, the regulation of its production is unclear. Recent data from podocyte-specific knockout mice suggest that VPF/VEGF-A is critical for the proper ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1111/j.1523-1755.2004.00910.x
更新日期:2004-10-01 00:00:00
abstract:BACKGROUND:Macrophage-mesangial cell interaction plays a crucial role in the pathogenesis of glomerulonephritis. We established a novel system for continuous, real-time monitoring of cross-talk between macrophages and mesangial cells in vitro and ex vivo. METHODS:Rat mesangial cells were genetically engineered to prod...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1111/j.1523-1755.2005.00471.x
更新日期:2005-08-01 00:00:00
abstract::Hyperlipidemia can induce or aggravate renal tubulointerstitial injury. Experiments in a complex rat model with chronic glomerulonephritis and long-standing, coexisting hyperlipidemia suggested that induction of xanthine oxidase (XO), with increased oxygen radical generation, is involved in aggravation of tubulointers...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/sj.ki.5000121
更新日期:2006-02-01 00:00:00
abstract:BACKGROUND:Elimination of residual proteinuria is the novel target in renoprotection; nevertheless, whether a greater suppression of renin-angiotensin system (RAS) effectively improves the antiproteinuric response in patients with moderate proteinuria remains ill-defined. METHODS:We evaluated the effects of maximizing...
journal_title:Kidney international
pub_type: 临床试验,杂志文章
doi:10.1046/j.1523-1755.2003.00015.x
更新日期:2003-06-01 00:00:00
abstract:BACKGROUND:Knowledge of the long-term renal prognosis of diarrhea associated hemolytic uremic syndrome (HUS) is important for patient counseling and follow-up. However, estimates of long-term risk are highly variable, with previous studies not using a healthy control group. METHODS:A municipal water system in the smal...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1111/j.1523-1755.2005.00225.x
更新日期:2005-04-01 00:00:00
abstract::Kidney disease is associated with increased cardiovascular morbidity, but underlying mechanisms are poorly understood. We tested the hypothesis that chronic renal insufficiency impairs angioadaptation in a rat model of hindlimb ischemia. Twenty male Sprague-Dawley rats (8 weeks old) underwent subtotal nephrectomy (5/6...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/sj.ki.5000448
更新日期:2006-06-01 00:00:00
abstract:BACKGROUND:The hypothesis that angiotensin-converting enzyme (ACE) inhibitors interfere with the treatment of anemia with recombinant human erythropoietin (rHuEPO) remains controversial. To test this hypothesis, a retrospective analysis was conducted in a large group of hemodialysis patients with renal anemia. METHODS...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2001.00028.x
更新日期:2001-11-01 00:00:00
abstract:BACKGROUND:There is growing evidence pointing to an involvement of cytokines and growth factors in renal osteodystrophy. In this study, the expression of interleukin-l beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), and basic fibroblast growth factor (bFGF) in bone...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2003.00835.x
更新日期:2003-03-01 00:00:00
abstract:UNLABELLED:Inhibition of pressure natriuresis in mice lacking the AT2 receptor. BACKGROUND:Angiotensin II type 2 (AT2) receptor knockout mice have higher blood pressures than wild-type mice; however, the hypertension is imperfectly defined. We tested the hypothesis that renal mechanisms could be contributory. METHODS...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2000.00820.x
更新日期:2000-01-01 00:00:00
abstract::Transient renal tubular acidosis may complicate acute renal failure (ARF). To clarify this phenomenon, the present study examined tubular H+ ion secretory capacity in an ischemic model of ARF. Clearance studies were performed in dogs subjected to 60 minutes, unilateral renal artery clamping. The contralateral kidney s...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1986.271
更新日期:1986-12-01 00:00:00
abstract:BACKGROUND:Antineutrophil cytoplasm antibodies (ANCAs) are implicated in the pathogenesis of systemic vasculitis. We asked whether ANCA could induce nitric oxide (NO) release from human neutrophils and, if so, whether this NO production was dependent on NO synthase (NOS) activity. METHODS:Neutrophil NO production was ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2001.059002593.x
更新日期:2001-02-01 00:00:00
abstract:BACKGROUND:The inhibitor of apoptosis (IAP) family of proteins regulates programmed cell death triggered by various stimuli. The purpose of this investigation was to examine the expression, regulation, and function of IAP genes in cultured rat mesangial cells. METHODS:Basal and inducible expression of c-IAP1, c-IAP2, ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2001.060002579.x
更新日期:2001-08-01 00:00:00
abstract::Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by dysregulated complement activation. Clinically, aHUS is effectively treated by an anti-C5 monoclonal antibody (mAb) but whether the disease is mediated by the C5a receptor (C5aR) or C5b-9 pathway, or both, is unknown. Her...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1016/j.kint.2019.01.009
更新日期:2019-07-01 00:00:00
abstract::As an alternative to classical immunosuppressants in experimental lupus nephritis, we looked at bindarit, 2-methyl-2-[[1-phenylmethyl)-1H-indazol-3-y1]methoxy]propanoic acid, a novel molecule devoid of immunosuppressive effects, which selectively reduces chronic inflammation in rat adjuvant arthritis. Two groups of NZ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1998.00804.x
更新日期:1998-03-01 00:00:00
abstract::Viral peritonitis is an exceptionally rare occurrence in peritoneal dialysis. In fact, up to now, only one case report has been documented in the literature. In a prospective study, peritoneal dialysis effluent (PDE) was specifically cultured for the following viruses: the herpes group of viruses, including herpes sim...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1989.191
更新日期:1989-08-01 00:00:00
abstract::Thrombomodulin (TM), an endothelial receptor for thrombin, endowed with a powerful anticoagulant activity, plays an important role in the antithrombogenicity of the vascular endothelium. Its presence within the human renal glomerulus is already known but was thought to be only endothelial. We looked for TM expression ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1997.99
更新日期:1997-03-01 00:00:00