The Cyclosporine A-Induced Decrease in Rat Renal Calbindin-D28kDa Protein as a Consequence of a Decrease in its mRNA

Grenet, Olivier; Varela, Maria del Carmen; Staedtler, Frank; Steiner, Sandra

doi:10.1016/s0006-2952(97)00646-1

Cited by 14 publications

(4 citation statements)

References 8 publications

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“…The study by Christakos and colleagues [27] indicates that renal calbindin-D28k expression is probably the best marker for the 1,25(OH)2D3 activity. Renal calbindin-D28k appears to enhance tubular Ca 2+ reabsorption, and a reduction of renal calbindin-D28k is associated with hypercalciuria [28][29][30][31][32]. Findings from a recent in vivo study using a gene-knockout model confirm the critical role of calbindin-D28k in maintaining renal calcium homeostasis [33].…”

Section: Discussionmentioning

confidence: 97%

Proteomic Identification and Immunolocalization of Increased Renal Calbindin-D28k Expression in OVE26 Diabetic Mice

Thongboonkerd¹,

Zheng²,

McLeish³

et al. 2005

Rev Diab Stud

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■ AbstractDiabetic nephropathy is a common diabetic complication that is associated with alterations in the expression of several renal proteins and abnormal calcium homeostasis. We performed proteomic analysis to screen for global changes of renal protein expression in diabetic kidney. Proteins extracted from the whole kidney of 120-day-old OVE26 (a transgenic model of Type 1 diabetes) and FVB (non-diabetic background strain) mice were separated by two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) and visualized by SYPRO Ruby staining (n = 5 in each group). Quantitative intensity analysis revealed 41 differentially expressed proteins, of which 30 were identified by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) followed by peptide mass fingerprinting. One of the altered proteins with the greatest magnitude of change was the calcium-binding protein, calbindin-D28k, whose expression was increased 6.7-fold in diabetic kidney. We confirmed the increase in calbindin-D28k expression in diabetic kidney by Western blot analysis. Immunohistochemical study demonstrated that calbindin-D28k expression was markedly increased in tubular epithelial cells of distal convoluted tubules (DCT), collecting ducts (CD), and proximal convoluted tubules (PCT) in diabetic kidney. Calbindin-D28k plays a critical role in maintaining calcium homeostasis. The elevation in renal calbindin-D28k expression in our model may indicate a compensatory mechanism to overcome hypercalciuria in diabetes.

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Section: Discussionmentioning

confidence: 97%

Proteomic Identification and Immunolocalization of Increased Renal Calbindin-D28k Expression in OVE26 Diabetic Mice

Thongboonkerd¹,

Zheng²,

McLeish³

et al. 2005

Rev Diab Stud

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“…Reverse transcription followed by polymerase chain reaction (RT-PCR) revealed that the CsA-mediated down-regulation of the renal calbindin-D 28 kDa protein is most likely the result of a decrease in the calbindin-D 28 kDa mRNA level [5]. Evidence was provided that the decrease in renal calbindin-D 28 kDa protein levels in rats is associated with increased urine calcium excretion and corticomedullary intratubular calcifications [6].…”

Section: Introductionmentioning

confidence: 99%

New insights into cyclosporine A nephrotoxicity by proteome analysis

et al. 1998

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Using two-dimensional gel electrophoresis (2-DE), we recently discovered an association between decreased calcium-binding protein, calbindin-D 28 kDa, urinary calcium wasting and intratubular corticomedullary calcifications in rat kidney. This observation prompted us to investigate kidney tissues of other species, including man. In this paper we show that in dogs and monkeys, which are generally devoid of cyclosporine A (CsA)-mediated nephrotoxicity, renal calbindin levels were not affected by the CsA treatment whereas in CsA-treated human kidney-transplant recipients with renal vascular or tubular toxicity, a marked decrease in renal calbindin-D 28 kDa protein level was found in most of the kidney biopsy sections. The present results strongly suggest that calbindin is a marker for CsA-nephrotoxicity. The discovery of calbindin-D 28 kDa being involved in CsA toxicity has evolved from the application of 2-DE and has not been reported previously, proving that proteomics can provide essential information in mechanistic toxicology. Considering the current improvements in proteome methods it is expected that high throughput proteomics will become an indispensable tool in preclinical safety testing.

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“…An improved understanding of the toxicity manifested in experimental animal models will improve the predictive accuracy of extrapolating from animal models to humans, and therefore, greatly reduce this source of uncertainty in the risk assessment process. For example, in our labs proteomics and quantitative RT-PCR played a key role in the mechanistic understanding of cyclosporine A (CsA) induced nephrotoxicity (28,74), which is a common side effect observed for immunosuppressant drugs. In kidneys of CsA-treated rats, a profound downregulation of the calcium binding protein calbindin-D28kDa was found to correlate with the accumulation of calcium in the tubules (Figure 1).…”

Section: Toxicogenomics Applicationsmentioning

confidence: 99%

“…The bars represent the means ± SD of 8-10 rats. From Grenet et al(28).are well characterized are now available for interrogation with expression profiles of candidate drugs. BioExpress (GeneLogic) is a repository of gene expression profiles from normal and diseased human tissue and experimental animal tissues treated with reference compounds.…”

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confidence: 99%

Toxicogenomics in Drug Development

et al. 2003

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Toxicogenomics represents the merging of toxicology with technologies that have been developed, together with bioinformatics, to identify and quantify global gene expression changes. It represents a new paradigm in drug development and risk assessment, which promises to generate a wealth of information towards an increased understanding of the molecular mechanisms that lead to drug toxicity and efficacy, and of DNA polymorphisms responsible for individual susceptibility to toxicity. Gene expression profiling, through the use of DNA microarray and proteomic technologies will aid in establishing links between expression profiles, mode of action and traditional toxic endpoints. Such patterns of gene expression, or 'molecular fingerprints' could be used as diagnostic or predictive markers of exposure, that is characteristic of a specific mechanism of induction of that toxic or efficacious effect. It is anticipated that toxicogenomics will be increasingly integrated into all phases of the drug development process particularly in mechanistic and predictive toxicology, and biomarker discovery. This review provides an overview of the expression profiling technologies applied in toxicogenomics, and discusses the promises as well as the future challenges of applying this discipline to the drug development process.Keywords. DNA microarrays; PCR; bioinformatics; gene expression profiling; genomics; proteomics; biomarkers; toxicology. INTRODUCTIONThe evolution of new innovative technologies in parallel with recent dramatic increases in genomic knowledge is anticipated to revolutionize toxicological studies by providing significant advances in the understanding and prediction of the toxicity and efficacy of new drugs (38, 39, 52). In classic toxicology, potential adverse effects resulting from drug exposure are evaluated using endpoints such as body and organ weight changes, biochemical and histopathological observations. Such observations, however, do not provide information about a drug's mode of action. To better evaluate the adverse effects associated with drug exposure, one needs to understand the drug's specific mode of action. Drugs are expected to induce a multitude of complex molecular perturbations in a wide variety of pathways, involving differential gene expression at the transcript and functional protein level, leading to efficacious and/or pathological outcomes. These changes in gene expression are often more sensitive and characteristic of the toxic response or process than currently employed endpoints of pathology, and have the potential to indicate toxicity already at lower doses or at earlier time points.Technological advances derived from genomic research have made it possible to follow transcriptional and translational events of genes and even the entire genome. The application of genome-wide expression profiling technologies to toxicology has created a new subdiscipline coined 'toxicogenomics,' which has the potential to provide a more comprehensive understanding of the mechanisms of pharmacology ...

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The Cyclosporine A-Induced Decrease in Rat Renal Calbindin-D28kDa Protein as a Consequence of a Decrease in its mRNA

Cited by 14 publications

References 8 publications

Proteomic Identification and Immunolocalization of Increased Renal Calbindin-D28k Expression in OVE26 Diabetic Mice

Proteomic Identification and Immunolocalization of Increased Renal Calbindin-D28k Expression in OVE26 Diabetic Mice

New insights into cyclosporine A nephrotoxicity by proteome analysis

Toxicogenomics in Drug Development

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