Promotion of oxidative stress in kidney of rats loaded with cystine dimethyl ester

Rech, Virgínia Cielo; Feksa, Luciane Rosa; Amaral, Maria Fernanda Arévalo do; Koch, Gustavo Waltereith; Wajner, Moaçir; Dutra-Filho, Carlos Severo; Wyse, Ângela Terezinha de Souza; Wannmacher, Clóvis Milton Duval

doi:10.1007/s00467-007-0494-2

Cited by 11 publications

(6 citation statements)

References 48 publications

(50 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is a highly coordinated gene set involved in oxidative phosphorylation in cystinosis (Table 2). It is interesting to observe these data, since production of ROS and induction of oxidative stress have previously been implicated in cystinosis (Rech et al 2007). Notably, an elevated glutathione disulfide to total glutathione ratio was reported in cystinotic cells, suggesting increased oxidative stress in cystinotic cells (Levtchenko et al 2005), and elevated oxidative stress has been associated with apoptosis (Corcoran et al 1994).…”

Section: Discussionmentioning

confidence: 93%

Insights into novel cellular injury mechanisms by gene expression profiling in nephropathic cystinosis

Sansanwal¹,

Li²,

Hsieh³

et al. 2010

J of Inher Metab Disea

View full text Add to dashboard Cite

Nephropathic cystinosis is a rare, inherited metabolic disease caused by functional defects of cystinosin associated with mutations in the CTNS gene. The mechanisms underlying the phenotypic alterations associated with this disease are not well known. In this study, gene expression profiles in peripheral blood of nephropathic cystinosis patients (N = 7) were compared with controls (N = 7) using microarray technology. In unsupervised hierarchical clustering analysis, cystinosis samples co-clustered, and 1,604 genes were significantly differentially expressed between both groups. Gene ontology analysis revealed that differentially expressed genes in cystinosis were enriched in cell organelles such as mitochondria, lysosomes, and endoplasmic reticulum (p ≤ 0.030). The majority of the differentially regulated genes were involved in oxidative phosphorylation, apoptosis, mitochondrial dysfunction, endoplasmic reticulum stress, antigen processing and presentation, B-cell-receptor signaling, and oxidative stress (p ≤ 0.003). Validation of selected genes involved in apoptosis and oxidative phosphorylation was performed by quantitative real-time polymerase chain reaction (PCR). Electron microscopy and confocal imaging of cystinotic renal proximal tubular epithelial cells further confirmed anomalies in the cellular organelles and pathways identified by microarray analysis. Further analysis of these genes and pathways may offer critical insights into the clinical spectrum of cystinosis patients and ultimately lead to novel links for targeted therapy.

show abstract

Section: Discussionmentioning

confidence: 93%

Insights into novel cellular injury mechanisms by gene expression profiling in nephropathic cystinosis

Sansanwal¹,

Li²,

Hsieh³

et al. 2010

J of Inher Metab Disea

View full text Add to dashboard Cite

show abstract

“…An obvious drawback in using CDME loading to achieve increased lysosomal cystine, pathognomonic of cystinotic cells, is that cystine disposal is carried out normally by the cells through their intact cystinosin (Wilmer et al 2007). It must be emphasized that in cystinosis, cystine accumulates in the lysosomes de novo , not by saturating the cytosol with excessive amounts of cystine as is the case in CDME loading (Rech et al 2007). In contrast, CTNS gene silencing provided us with a model mimicking the basic genetic defect in cystinosis, which resulted in increased intracellular cystine, indicating that the storage defect in this in vitro model is preserved.…”

Section: Discussionmentioning

confidence: 99%

Cystine dimethylester loading promotes oxidative stress and a reduction in ATP independent of lysosomal cystine accumulation in a human proximal tubular epithelial cell line

Sumayao

McEvoy

Martín-Martín

et al. 2013

Experimental Physiology

View full text Add to dashboard Cite

New findingsr What is the central question of this study?Are the molecular and cellular consequences of cystine dimethylester loading different from an alternative and more specific model of the cystinotic kidney proximal tubule epithelial cell, obtained by CTNS gene silencing. r What is the main finding and its importance?Using a human-derived kidney proximal tubular cell line, HK-2, we demonstrated that cystine dimethylester loading induces detrimental effects independent of lysosomal cystine accumulation. CTNS gene silencing, which resulted in comparable levels of cystine accumulation, evidence of oxidative stress and reduced ATP concentration but unaltered ATP generation capacity, represents a more useful model for investigating biochemical alterations in cystinosis.Using the cystine dimethylester (CDME) loading technique to achieve elevated lysosomal cystine levels, ATP depletion has previously been postulated to be responsible for the renal dysfunction in cystinosis, a genetic disorder characterized by an excessive accumulation of cystine in the lysosomes. However, this is unlikely to be the sole factor responsible for the complexity of cell stress associated with cystinosis. Moreover, CDME has been shown to induce a direct toxic effect on mitochondrial ATP generation. Using a human-derived proximal tubular epithelial cell line, we compared the effects of CDME loading with small interfering RNA-mediated cystinosin, lysosomal cystine transporter (CTNS) gene silencing on glutathione redox status, reactive oxygen species levels, oxidative stress index, antioxidant enzyme activities and ATP generating capacity. The CDME-loaded cells displayed increased total glutathione content, extensive superoxide depletion, augmented oxidative stress index, decreased catalase activity, normal superoxide dismutase activity and compromised ATP generation. In contrast, cells subjected to CTNS gene inhibition demonstrated decreased total glutathione content, increased superoxide levels, unaltered oxidative stress index, unaltered catalase activity, induction of superoxide dismutase activity and normal ATP generation. Our data indicate that many CDME-induced effects are independent of lysosomal cystine accumulation, which further underscores the limited value of CDME loading for studying the pathogenesis of cystinosis. CTNS gene inhibition, which results C

show abstract

“…More specifically, cystinosis is a disease that results in renal proximal tubular dysfunction and defective transport of cystine across the lysosomal membrane (293). The accumulation of intracellular cystine induces oxidative stress and reduces mitochondrial ATP generation, leading to PTC damage and apoptosis (248). The loss of renal PTCs leads to Fanconi syndrome, decreased activity of Na + /K + ATPase activity in the proximal tubule, and ensuing attenuation of tubular transport of glucose, amino acids, electrolytes, and water (18,76).…”

Section: Genetic Tubular Diseasesmentioning

confidence: 99%

Oxidant Mechanisms in Renal Injury and Disease

Ratliff

Abdulmahdi

Pawar

et al. 2016

Antioxidants & Redox Signaling

533

513

View full text Add to dashboard Cite

Significance: A common link between all forms of acute and chronic kidney injuries, regardless of species, is enhanced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during injury/ disease progression. While low levels of ROS and RNS are required for prosurvival signaling, cell proliferation and growth, and vasoreactivity regulation, an imbalance of ROS and RNS generation and elimination leads to inflammation, cell death, tissue damage, and disease/injury progression. Recent Advances: Many aspects of renal oxidative stress still require investigation, including clarification of the mechanisms which prompt ROS/ RNS generation and subsequent renal damage. However, we currently have a basic understanding of the major features of oxidative stress pathology and its link to kidney injury/disease, which this review summarizes. Critical Issues: The review summarizes the critical sources of oxidative stress in the kidney during injury/ disease, including generation of ROS and RNS from mitochondria, NADPH oxidase, and inducible nitric oxide synthase. The review next summarizes the renal antioxidant systems that protect against oxidative stress, including superoxide dismutase and catalase, the glutathione and thioredoxin systems, and others. Next, we describe how oxidative stress affects kidney function and promotes damage in every nephron segment, including the renal vessels, glomeruli, and tubules. Future Directions: Despite the limited success associated with the application of antioxidants for treatment of kidney injury/disease thus far, preventing the generation and accumulation of ROS and RNS provides an ideal target for potential therapeutic treatments. The review discusses the shortcomings of antioxidant treatments previously used and the potential promise of new ones.

show abstract

Promotion of oxidative stress in kidney of rats loaded with cystine dimethyl ester

Cited by 11 publications

References 48 publications

Insights into novel cellular injury mechanisms by gene expression profiling in nephropathic cystinosis

Insights into novel cellular injury mechanisms by gene expression profiling in nephropathic cystinosis

Cystine dimethylester loading promotes oxidative stress and a reduction in ATP independent of lysosomal cystine accumulation in a human proximal tubular epithelial cell line

Oxidant Mechanisms in Renal Injury and Disease

Contact Info

Product

Resources

About