Cisplatin-induced rat model of kidney injury: physiological, functional, histological and gene expression profile evaluations
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE140601 | GEO | 2021/02/15
REPOSITORIES: GEO
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Project description:In hepatic dysfunction, renal pharmacokinetic adaptation can be observed, although information on the changes in drug exposure and the interorgan regulation of membrane transporters in kidney in liver diseases is limited. This study aimed to clarify the effects of renal exposure to nephrotoxic drugs during cholestasis induced by bile duct ligation (BDL). Among the 11 nephrotoxic drugs examined, the tissue accumulation of imatinib and cisplatin in kidney slices obtained from mice 2 weeks after BDL operation was higher than that in sham-operated mice. The uptake of imatinib in the kidney slices of BDL mice was slightly higher, whereas its efflux from the slices was largely decreased compared to that in sham-operated mice. Proteomic analysis revealed a reduction in renal expression of the efflux transporter multidrug resistance-associated protein 6 (Mrp6/Abcc6) in BDL mice, and both imatinib and cisplatin were identified as Mrp6 substrates. Survival probability after cisplatin administration was reduced in BDL mice. In conclusion, the present study demonstrated that BDL-induced cholestasis leads to the downregulation of the renal basolateral efflux transporter Mrp6, resulting in drug accumulation in renal cells and promoting drug-induced renal injury.
2023-08-22 | GSE212283 | GEO
Project description:Clinical use of a major cancer chemotherapeutic agent, cisplatin, is restricted to dose-limiting renal toxicity. A transcriptomic approach enabled us to extract putative molecules including Pleckstrin homology-like domain, family A, member-3 (Phlda3) contributing to the renal injury. This study investigated the expression of Phlda3 and its regulatory role in tubular injury induced by cisplatin in vivo and in vitro. Real-time PCR and immunoblot assays confirmed that Phlda3 was highly up-regulated in the kidney of mice after a single dose of cisplatin treatment, which preceded increases in the blood urea nitrogen or serum creatinine levels. Particularly, the level of Phlda3 transcript was substantially increased at an early time than that of kidney injury molecule-1, and remained elevated. The effect of cisplatin or acetaminophen treatment on Phlda3 expression in the liver was minimal. Consistently, treatment of NRK52E, a renal tubular cell line, with cisplatin caused increases in Phlda3 mRNA and protein. Knockdown of Phlda3 reversed the decrease in cell viability by cisplatin, supporting the role of Phlda3 in cell death. Akt phosphorylation initially increased after cisplatin treatment, but decreased thereafter. Cisplatin treatment elicited p53 accumulation via mdm2 repression, inducing its target genes, p21 and cyclin G1. Phlda3 deficiency attenuated a decrease in Akt phosphorylation by cisplatin, and prevented p53 accumulation, supporting the role of Phlda3 for p53-mediated tubular cell death. Other renal toxicants, cyclosporine A and CdCl2, also enhanced Phlda3-dependent cell death. Overall, nephrotoxicants including cisplatin induce Phlda3, which leads to p53-mediated tubular cell death via mdm2 repression caused by Akt inhibition. Since the datasets reported on the effect of cisplatin on the kidney were obtained from animals treated with multiple and relatively high doses of cisplatin, we did our cDNA array analyses day 3 after a single dose of cisplatin administration to mice (i.p., 15 mg/kg) and compared the profiles of kidney microarray data. The transcriptomic approach enabled us to find the putative genes encoding molecules contributing to renal injury. Among those genes represented on the microarray, 33 genes were found to be differentially expressed by cisplatin treatment when a 2-fold change cutoff was used. The regulation of exemplary mRNAs identified in the array analysis was confirmed by qRT-PCR. C57BL/6 mice (9 weeks old) were intraperitoneally injected with a single dose of cisplatin (15 mg/kg body weight) or vehicle (saline). The cDNA microarray experiments were done for the kidney of mice 3 days after treatment. Each group contained 3 males.
2012-06-29 | E-GEOD-35257 | biostudies-arrayexpress
Project description:Background The mysterious chronic kidney disease is multifactorial causes. One of the risk factors is leptospirosis, a re-emerging infectious disease caused by Leptospira spp., for endemic leptospirosis tend to coincide with high-incidence regions of chronic kidney disease of unknown etiology. This study aims to investigate the role of leptospirosis as an emerging culprit in which chronic subclinical kidney injury, may predispose to progressive kidney disease when superimposed on secondary nephrotoxic injury. Methods Adenine-induced renal injury in chronic leptospira-infected C57/BL6 mice were studied for evaluating the renal function, histology and gene expression changes. We employed RNA sequencing-based renal transcriptome to investigate pathogenic pathways associated with secondary nephrotoxic injury in chronic kidney injury due to leptospirosis. Results The severity of kidney lesions was increased and the expression of immune/inflammation/fibrosis genes were significantly up-regulated in either low-dose (0.1%) and high-dose (0.2%) adenine-induced renal injury superimposed on infected mice. Whole renal transcriptome analysis reveals that the substantial amplification of the tremendous amount of expressed genes and fibrosis-related pathways was found in adenine-induced kidney injury add-on to leptospira-infected mice which correlated with kidney dysfunction and fibrosis compared to infection or adenine itself. A total of 41 differentially expressed genes associated with fibrosis were identified in infected mice fed with adenine, suggesting that these potential genes contributed to aggravated renal progression occurred in adenine-fed chronic leptospira-infected mice. Conclusions In summary, this study indicates that chronic subclinical kidney infection when exposed to different degree of secondary nephrotoxic injury may predispose to exacerbated and progressive chronic kidney disease.
2021-04-05 | GSE150641 | GEO
Project description:We are interested in the inner medulla of the kidney and how the nephrotoxic drug, cisplatin, may affect the transcriptome. Furthermore, we are interested in male and female inner medullary transcriptomic differences.
2023-01-01 | GSE195786 | GEO
Project description:Clinical use of a major cancer chemotherapeutic agent, cisplatin, is restricted to dose-limiting renal toxicity. A transcriptomic approach enabled us to extract putative molecules including Pleckstrin homology-like domain, family A, member-3 (Phlda3) contributing to the renal injury. This study investigated the expression of Phlda3 and its regulatory role in tubular injury induced by cisplatin in vivo and in vitro. Real-time PCR and immunoblot assays confirmed that Phlda3 was highly up-regulated in the kidney of mice after a single dose of cisplatin treatment, which preceded increases in the blood urea nitrogen or serum creatinine levels. Particularly, the level of Phlda3 transcript was substantially increased at an early time than that of kidney injury molecule-1, and remained elevated. The effect of cisplatin or acetaminophen treatment on Phlda3 expression in the liver was minimal. Consistently, treatment of NRK52E, a renal tubular cell line, with cisplatin caused increases in Phlda3 mRNA and protein. Knockdown of Phlda3 reversed the decrease in cell viability by cisplatin, supporting the role of Phlda3 in cell death. Akt phosphorylation initially increased after cisplatin treatment, but decreased thereafter. Cisplatin treatment elicited p53 accumulation via mdm2 repression, inducing its target genes, p21 and cyclin G1. Phlda3 deficiency attenuated a decrease in Akt phosphorylation by cisplatin, and prevented p53 accumulation, supporting the role of Phlda3 for p53-mediated tubular cell death. Other renal toxicants, cyclosporine A and CdCl2, also enhanced Phlda3-dependent cell death. Overall, nephrotoxicants including cisplatin induce Phlda3, which leads to p53-mediated tubular cell death via mdm2 repression caused by Akt inhibition. Since the datasets reported on the effect of cisplatin on the kidney were obtained from animals treated with multiple and relatively high doses of cisplatin, we did our cDNA array analyses day 3 after a single dose of cisplatin administration to mice (i.p., 15 mg/kg) and compared the profiles of kidney microarray data. The transcriptomic approach enabled us to find the putative genes encoding molecules contributing to renal injury. Among those genes represented on the microarray, 33 genes were found to be differentially expressed by cisplatin treatment when a 2-fold change cutoff was used. The regulation of exemplary mRNAs identified in the array analysis was confirmed by qRT-PCR.
2012-06-30 | GSE35257 | GEO
Project description:Although there is significant progress in understanding the structure and function of NLRC5, a member of the NOD like receptor (NLR) family, in the context of MHC class I gene expression, the functions of NLRC5 in innate and adaptive immune responses beyond the regulation of MHC class I genes remain controversial and unresolved. In particular, the role of NLRC5 in the kidney keeps unknown. In this study, we found that NLRC5 was significantly upregulated in the kidney from mice with renal ischemia/reperfusion injury (IRI). NLRC5 deficient (NLRC5-/-) mice significantly ameliorated renal injury as evidenced by decreased serum creatinine levels, improved morphological injuries, and reduced inflammatory responses versus wild type mice. Similar protective effects were also observed in cisplatin-induced acute kidney injury (AKI). Mechanistically, NLRC5 contributed to renal injury by promoting tubular epithelial cell apoptosis and reducing inflammatory responses which is associated with, at least in part, the negative regulation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). To determine the relative contribution of NLRC5 expression by parenchymal cells or leukocytes to renal damage during IRI, we generated bone marrow (BM) chimeric mice. NLRC5-/- mice engrafted with WT hematopoietic cells had significantly lower serum creatinine and less tubular damage than WT mice reconstituted with NLRC5-/- BM, suggesting that NLRC5 signaling in renal parenchymal cells plays the dominant role in mediating renal damage. Collectively, modulation of NLRC5-mediated pathway may have important therapeutic implications for patients with AKI.
2018-01-19 | GSE109374 | GEO
Project description:Although Tacrolimus is an immunosuppressive drug widely used in renal transplantation, its chronic use paradoxically induces nephrotoxic effects, in particular renal fibrosis, which is responsible for chronic allograft dysfunction and represents a major prognostic factor of allograft survival. As molecular pathways and mechanisms involved in Tacrolimus-induced fibrogenic response are poorly elucidated, we assessed whether miRNAs are involved in the nephrotoxic effects mediated by Tacrolimus. Treatment of CD-1 mice with Tacrolimus (1mg/kg/d for 28 days) resulted in kidney injury and was associated with alteration of a gene expression signature associated with cellular stress, fibrosis and inflammation. Tacrolimus also affected renal miRNA expression, including miRNAs previously involved in fibrotic and inflammatory processes including “fibromirs” such as miR-21-5p. Specifically, Renal Proximal Tubular Epithelial cells exposed to tacrolimus showed up-regulation of miR-21-5p and the concomitant induction of epithelial phenotypic changes, inflammation and oxidative stress. In conclusion, this study suggests for the first time that miRNAs, especially fibromiRs, mediate Tacrolimus-induced nephrotoxic effects.
2018-02-06 | GSE102514 | GEO
Project description:Although Tacrolimus is an immunosuppressive drug widely used in renal transplantation, its chronic use paradoxically induces nephrotoxic effects, in particular renal fibrosis, which is responsible for chronic allograft dysfunction and represents a major prognostic factor of allograft survival. As molecular pathways and mechanisms involved in Tacrolimus-induced fibrogenic response are poorly elucidated, we assessed whether miRNAs are involved in the nephrotoxic effects mediated by Tacrolimus. Treatment of CD-1 mice with Tacrolimus (1mg/kg/d for 28 days) resulted in kidney injury and was associated with alteration of a gene expression signature associated with cellular stress, fibrosis and inflammation. Tacrolimus also affected renal miRNA expression, including miRNAs previously involved in fibrotic and inflammatory processes including “fibromirs” such as miR-21-5p. Specifically, Renal Proximal Tubular Epithelial cells exposed to tacrolimus showed up-regulation of miR-21-5p and the concomitant induction of epithelial phenotypic changes, inflammation and oxidative stress. In conclusion, this study suggests for the first time that miRNAs, especially fibromiRs, mediate Tacrolimus-induced nephrotoxic effects.
2018-02-06 | GSE102513 | GEO
Project description:Previous studies have suggested that CD133+ cells isolated from human kidney biopsies have the potential to ameliorate injury following intravenous (IV) administration in rodent models of kidney disease by integrating into damaged renal tissue and generating specialised renal cells. However, whether renal engraftment of CD133+ cells is prerequisite for ameliorating injury has not yet been unequivocally resolved. Here, we have established a cisplatin-induced nephropathy model in immunodeficient rats to assess the efficacy of CD133+ human kidney cells in restoring renal health, and to determine the fate of these cells after systemic administration. Specifically, following IV administration, we evaluated the impact of the CD133+ cells on renal function by undertaking longitudinal measurements of the glomerular filtration rate using a novel transcutaneous device. Furthermore, using histological assays, we assessed whether the human kidney cells could promote renal regeneration, and if this was related to their ability to integrate into the damaged kidneys. Our results show that both CD133+ and CD133- cells improve renal function and promote renal regeneration to a similar degree. However, this was not associated with engraftment of the cells into the kidneys. Instead, after IV administration, both cell types were exclusively located in the lungs, and had disappeared by 24 hours. Our data therefore indicate that renal repair is not mediated by CD133+ cells homing to the kidneys and generating specialised renal cells. Instead, renal repair is likely to be mediated by paracrine or endocrine factors.
2017-05-02 | GSE90628 | GEO
Project description:Although Tacrolimus is an immunosuppressive drug widely used in renal transplantation, its chronic use paradoxically induces nephrotoxic effects, in particular renal fibrosis, which is responsible for chronic allograft dysfunction and represents a major prognostic factor of allograft survival. As molecular pathways and mechanisms involved in Tacrolimus-induced fibrogenic response are poorly elucidated, we assessed whether miRNAs are involved in the nephrotoxic effects mediated by Tacrolimus. Treatment of CD-1 mice with Tacrolimus (1mg/kg/d for 28 days) resulted in kidney injury and was associated with alteration of a gene expression signature associated with cellular stress, fibrosis and inflammation. Tacrolimus also affected renal miRNA expression, including miRNAs previously involved in fibrotic and inflammatory processes including “fibromirs” such as miR-21-5p. Specifically, Renal Proximal Tubular Epithelial cells exposed to tacrolimus showed up-regulation of miR-21-5p and the concomitant induction of epithelial phenotypic changes, inflammation and oxidative stress. In conclusion, this study suggests for the first time that miRNAs, especially fibromiRs, mediate Tacrolimus-induced nephrotoxic effects. This SuperSeries is composed of the SubSeries listed below.
2018-02-06 | GSE102515 | GEO