Abstract:
BACKGROUND:The mechanisms of cyclosporine (CsA)-induced nephrotoxicity are not fully understood. While hemodynamic changes may be involved in vivo, there is also some evidence for tubular involvement. We previously showed direct toxicity of CsA in the LLC-PK1 renal tubular cell line. In the current study we examined mechanisms (apoptosis or necrosis) of cell death induced by CsA in the LLC-PK1 renal proximal tubular cell line. The possible role of the Fas (APO-1/CD95) antigen-Fas ligand system in the mediation of CsA-induced cell death was also investigated. METHODS:Cells were treated with CsA (0.42 nM to 83 microM) for 24 hours and alterations in DNA and protein synthesis and membrane integrity were examined. Flow cytometry was used to investigate: (i) alterations in the DNA content and cell cycle; (ii) the forward (FSC) and side (SSC) light scattering properties (indicators of cell size and granularity, respectively); (iii) the externalization of phosphatidylserine (PS) as a marker of early apoptosis using FITC-annexin V binding; and (iv) expression of the apoptotic Fas protein. DNA fragmentation in apoptotic cells was also determined by the TUNEL assay. RESULTS:CsA (all doses) caused a block in the G0/G1 phase of the cell cycle as indicated by a decrease in DNA synthesis and supported by an increase in the % of cells in the G0/G1 phase with concurrent decreases of those in the S and G2/M phases. The effect on protein synthesis appeared to be much less. Lower doses of CsA (4.2 nM) caused the appearance of a "sub-G0/G1" peak, indicative of reduced DNA content, on the DNA histogram that was paralleled by a reduction in cell size and an increased cell granularity and an increase in FITC-annexin V binding. DNA fragmentation was evident in these cells as assessed using the TUNEL assay. Higher doses of CsA increased cell size and decreased cell granularity and reduced membrane integrity. Expression of Fas, the cell surface molecule that stimulates apoptosis, was increased following low dose CsA exposure. CONCLUSIONS:These results indicate that CsA is directly toxic to LLC-PK1 cells with reduced DNA synthesis and cell cycle blockade. The mode of cell death, namely apoptosis or necrosis, is dose dependent. Fas may be an important mediator of CsA induced apoptosis in renal proximal tubular cells.
journal_name
Kidney Intjournal_title
Kidney internationalauthors
Healy E,Dempsey M,Lally C,Ryan MPdoi
10.1046/j.1523-1755.1998.00202.xsubject
Has Abstractpub_date
1998-12-01 00:00:00pages
1955-66issue
6eissn
0085-2538issn
1523-1755pii
S0085-2538(15)30832-2journal_volume
54pub_type
杂志文章abstract::The hormonal responsiveness profile of the cortical collecting duct varies from one species to another. To identify the hormones and agonists that modulate the functions of this tubule segment in the human species, we generated a cell line (HCD) immortalized by SV40 virus. The tubular origin of this cell line was asse...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1995.186
更新日期:1995-05-01 00:00:00
abstract::Many renal diseases are associated with fibrin deposition in the glomeruli, a situation that reflects an abnormality in the balance between the coagulation and fibrinolytic systems. We recently demonstrated that normal mouse kidney contains very low levels of type 1 plasminogen activator inhibitor (PAI-1), a potent an...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1995.17
更新日期:1995-01-01 00:00:00
abstract:BACKGROUND:Redox-active iron can promote oxidative stress and tissue injury by catalyzing hydroxyl radical generation and lipid peroxidation. Intravenous iron preparations are routinely administered in conjunction with erythropoietin to treat anemia in patients with chronic renal failure (CRF), a condition that is mark...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1111/j.1523-1755.2004.00580.x
更新日期:2004-05-01 00:00:00
abstract:BACKGROUND:Epithelial cells in the renal inner medulla accumulate osmolytes such as betaine to maintain normal cell volume during prolonged extracellular hypertonic stress. Betaine accumulation is the result of activation of transcription of the BGT1 transporter gene followed by increased betaine transport. METHODS:We...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2001.00733.x
更新日期:2001-06-01 00:00:00
abstract::Sodium thiosulfate, a reversible oxidation product of hydrogen sulfide, has vasodilating and anti-oxidative properties, making it an attractive agent to alleviate damaging effects of hypertension. In experimental settings, inhibition of nitric oxide synthase causes hypertension, renal dysfunction and damage. We hypoth...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1016/j.kint.2020.02.020
更新日期:2020-08-01 00:00:00
abstract::Innate lymphoid cells are a recently recognized group of immune cells with critical roles in tissue homeostasis and inflammation. Regulatory innate lymphoid cells are a newly identified subset of innate lymphoid cells, which play a suppressive role in the innate immune response, favoring the resolution of intestinal i...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1016/j.kint.2019.07.019
更新日期:2020-01-01 00:00:00
abstract:BACKGROUND:In renal cells, hyperosmolarity has been shown to induce the accumulation of myo-inositol, via the Na+/myo-inositol cotransporter (SMIT). Previously we showed that SMIT mRNA in the kidney is localized in the medullary thick ascending limb of Henle (TALH). Here we used renal cells derived from the rabbit oute...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1999.00235.x
更新日期:1999-01-01 00:00:00
abstract::The increasing use of mice in renal and cardiovascular studies has necessitated adapting physiological methods used for rats to mice, which are far smaller in size. We have adapted measurements of continuous renal blood flow, pressure natriuresis and diuresis, and laser-Doppler cortical and medullary flow to 40 g mice...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1997.462
更新日期:1997-11-01 00:00:00
abstract::In vitro metabolic acidosis (Met) induces greater bone mineral resorption than respiratory acidosis (Resp). Met, but not Resp, inhibits osteoblasts which control many aspects of osteoclastic function. To determine whether at a similar decrement in extracellular pH, Met and Resp would induce different changes in intrac...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1995.247
更新日期:1995-06-01 00:00:00
abstract::To maintain nitrogen equilibrium when prescribed a low protein diet (LPD), metabolic adaptations occur involving a reduction protein turnover, principally decreased muscle protein degradation. Studies suggest that in patients with chronic renal failure (CRF) uncomplicated by metabolic acidosis (MA), these adaptive res...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1991.275
更新日期:1991-10-01 00:00:00
abstract::The transforming growth factor-beta (TGF-beta) plays a central role in the progression of renal fibrosis. TGF-beta transduces its signal through the activin receptor-like kinase (ALK)5. IN-1130, a novel small molecule ALK5 inhibitor, inhibited the purified kinase domain of ALK5-mediated Smad3 phosphorylation with an I...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/sj.ki.5001775
更新日期:2006-10-01 00:00:00
abstract::Chronic balance studies were performed in six adrenalectomized patients to investigate the renal and systemic acid-base consequences of mineralocorticoid deficiency in the absence of either glucocorticoid deficiency or parenchymal renal disease. Constant glucocorticoid replacement was provided with dexamethasone, 750 ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1980.195
更新日期:1980-12-01 00:00:00
abstract::Vascular calcification (VC) is an important reason for the high burden of vascular disease among chronic dialysis patients. Chronic kidney disease (CKD) is associated with increased promoters and decreased inhibitors of VC. The circulating levels of fetuin-A, a well-described inhibitor of calcification, regulate the c...
journal_title:Kidney international
pub_type: 评论,杂志文章,评审
doi:10.1038/sj.ki.5002355
更新日期:2007-07-01 00:00:00
abstract::Problems with vascular access are an important cause of morbidity and mortality in hemodialysis patients. We established a rodent model of arteriovenous fistula by anastomosing the end of a lateral vein to the side of the ventral artery of the rat tail. All operations were technically successful and in all animals the...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2008.207
更新日期:2008-08-01 00:00:00
abstract::The members of the matrix metalloproteinase gene family play critical roles in numerous physiologic events, including cellular migration, tissue remodeling in wound healing and development, as well as in the evolution of the inflammatory process. The 72 kDa gelatinase A (formerly denoted 72 kDa Type IV collagenase) is...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1038/ki.1997.191
更新日期:1997-05-01 00:00:00
abstract::beta 2-microglobulin-related amyloidosis (A beta 2M) represents a frequent complication in long-term dialysis patients. Although the pathogenetic mechanism has yet to be fully understood, it is known that amyloid fibrils usually consist of intact molecules of beta 2-microglobulin (beta 2m). Plasma proteinase inhibitor...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1992.368
更新日期:1992-10-01 00:00:00
abstract::Cytokines are important modulators of inflammation. The balance between pro- and anti-inflammatory cytokines determines whether the intensity of inflammatory response is within physiological limits or in the pathological range. The cytokine network is highly complex, containing interactive cascades of gene activation ...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1038/sj.ki.5002391
更新日期:2007-09-01 00:00:00
abstract::Progression of diabetic nephropathy appears directly related to renal tubulointerstitial injury, but the involved genes are incompletely delineated. To identify such genes, DNA microarray analysis was performed with RNA from renal proximal tubules (RPTs) of streptozotocin-induced diabetic Wistar rats, spontaneously di...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/sj.ki.5000206
更新日期:2006-03-01 00:00:00
abstract::Ambient glucose concentrations alter type 1 angiotensin II receptor (AT1R) expression in renal tissues. The direction of change in AT1R density may depend on the specific cell type and the capacity for that cell type to use glucose as an energy substrate. Given the effects of angiotensin II (Ang II) in proximal tubule...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1997.307
更新日期:1997-07-01 00:00:00
abstract::We evaluated the contribution of intrarenal factors in the increased renal accumulation of bovine serum albumin (BSA) in chronic serum sickness (CSS). Renal transplantation was used to study 125I BSA uptake (single and paired label techniques) in normal and CSS kidneys exposed to the same immunologic milieu. In CSS, t...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1986.244
更新日期:1986-11-01 00:00:00
abstract::Autosomal dominant polycystic kidney disease (ADPKD) is a renal hereditary disorder associated with increased cardiovascular mortality, due to mutations in polycystin-1 and polycystin-2 genes. Endothelial polycystin-deficient cells have an altered mechanosensitivity to fluid shear stress and subsequent deficit in calc...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2014.241
更新日期:2015-02-01 00:00:00
abstract::The presence of CR1 mRNA in podocytes was investigated using a 35S-labeled CR1 cDNA probe and in situ hybridization in sections from fetal and adult human kidneys. CR1 mRNA was only detected in immature podocytes at early stages of glomerular differentiation in the fetal kidney. In contrast, CR1 antigen was abundantly...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1990.198
更新日期:1990-08-01 00:00:00
abstract::Early identification of kidney transplant recipients at risk of progressive allograft dysfunction may allow clinicians to provide closer monitoring and more aggressive risk factor modification. In this issue, Raynaud et al. presented a latent class model that clustered kidney transplant recipients into 8 risk categori...
journal_title:Kidney international
pub_type: 评论,杂志文章
doi:10.1016/j.kint.2020.07.031
更新日期:2021-01-01 00:00:00
abstract::To investigate whether the administration of cimetidine can improve the reliability of creatinine as a marker of GFR, we compared the creatinine clearance (CCr) to the clearance of the true filtration markers 51Cr-EDTA (CEDTA) and inulin (CIn), after oral ingestion of cimetidine in 10 healthy men and 29 patients with ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1991.331
更新日期:1991-12-01 00:00:00
abstract:BACKGROUND:Alterations of large artery function and structure are frequently observed in renal allograft recipients. However, endothelial function has not yet been assessed in this population. METHODS:Flow-mediated vasodilation is a useful index of endothelial function. We measured the diameter and distensibility of t...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1999.0550031104.x
更新日期:1999-03-01 00:00:00
abstract:BACKGROUND:The continuous chemical, physical, and inflammatory insults of prolonged continuous ambulatory peritoneal dialysis (CAPD) incite mesothelial cell responses, which may result in peritoneal fibrosis. The transforming growth factor-beta (TGF-beta), especially the isoform TGF-beta 1, has long been known to play ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2003.00861.x
更新日期:2003-04-01 00:00:00
abstract::The relationship between body mass index (BMI) and end-stage renal disease (ESRD) is confounded by co-morbidities associated with both conditions. Furthermore, the association at low range BMI is controversial. We studied this association in the Singapore Chinese Health Study, a population-based prospective cohort tha...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1016/j.kint.2017.03.019
更新日期:2017-10-01 00:00:00
abstract:BACKGROUND:Bioimpedance, a noninvasive technique to analyze body composition, has attracted interest in determining body hydration in hemodialysis patients. However, the so-called whole-body (wrist-to-ankle) bioimpedance analysis (WBIA) is sensitive to changes in regional fluid distribution and tends to underestimate f...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1999.00588.x
更新日期:1999-08-01 00:00:00
abstract::Conventional peritoneal dialysis (PD) fluids are known to inhibit polymorphonuclear cells (PMN) phagocytosis, oxidative burst and enzyme release. However, the relative contributions of apoptosis and/or necrosis to this dysfunction have not been examined. We investigated the effects of osmolality, glucose concentration...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1997.495
更新日期:1997-12-01 00:00:00
abstract::The soluble urokinase receptor (suPAR) promotes proteinuria and induces focal segmental glomerulosclerosis (FSGS)-like lesions in mice. A serum suPAR concentration cutoff of 3000 pg/ml has been proposed as a clinical biomarker for patients with FSGS. Interestingly, several studies in patients with glomerulopathy found...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2013.505
更新日期:2014-03-01 00:00:00