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Gordon C. Hard - One of the best experts on this subject based on the ideXlab platform.
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Renal histopathology in toxicity and carcinogenicity studies with tert butyl alcohol administered in drinking water to f344 rats a pathology working group review and re evaluation
Regulatory Toxicology and Pharmacology, 2011Co-Authors: Gordon C. Hard, Richard H Bruner, Samuel Monroe Cohen, John M Pletcher, Karen S ReganAbstract:Abstract An independent Pathology Working Group (PWG) re-evaluated the kidney changes in National Toxicology Program (NTP) toxicology/carcinogenicity studies of tert -butyl alcohol (TBA) in F344/N rats to determine possible mode(s) of action underlying Renal Tubule tumors in male rats at 2-years. In the 13-week study, the PWG confirmed that the normal pattern of round hyaline droplets in proximal convoluted Tubules was replaced by angular droplet accumulation, and identified precursors of granular casts in the outer medulla, changes typical of alpha 2u -globulin (α 2u -g) nephropathy. In the 2-year study, the PWG confirmed the NTP observation of increased Renal Tubule tumors in treated male groups. Linear papillary mineralization, another hallmark of the α 2u -g pathway was present only in treated male rats. Chronic progressive nephropathy (CPN) was exacerbated in high-dose males and females, with a relationship between advanced grades of CPN and Renal tumor occurrence. Hyperplasia of the papilla lining was a component of CPN in both sexes, but there was no pelvic urothelial hyperplasia. High-dose females showed no TBA-related nephrotoxicity. The PWG concluded that both α 2u -g nephropathy and exacerbated CPN modes of action were operative in TBA Renal tumorigenicity in male rats, neither of which has relevance for human cancer risk.
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Re-evaluation of the 2-year chloroform drinking water carcinogenicity bioassay in Osborne-Mendel rats supports chronic Renal Tubule injury as the mode of action underlying the Renal tumor response
2000Co-Authors: Gordon C. Hard, Gary A. Boorman, Douglas C. WolfAbstract:Chloroform, generally regarded as a non-genotoxic compound, is associated with the induction of liver and/or kidney tumors in labo-ratory mice and rats. In particular, chloroform produced Renal Tubule tumors in low incidence in male Osborne-Mendel rats when admin-istered by corn-oil gavage or in the drinking water. There is a lack of data on intermediate endpoints that may be linked to Renal cancer development in this strain of rat, in contrast to mice. Specifically, evidence linking chloroform-induced liver and kidney tumors in mice with cytotoxicity and regenerative cell proliferation is very strong, but weak in the rat. In the present study, kidney tissue from a carcino-genicity bioassay of chloroform in Osborne-Mendel rats was re-eval-uated for histological evidence of compound-induced cytotoxicity and cell turnover. All rats treated with 1800 ppm (160 mg/kg/day, high-dose group) in the drinking water for 2 years and half the rats treated with 900 ppm (81 mg/kg/day) had mild to moderate changes i
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Hazard evaluation of chemicals that cause accumulation of alpha 2u-globulin, hyaline droplet nephropathy, and Tubule neoplasia in the kidneys of male rats.
Environmental health perspectives, 1993Co-Authors: Gordon C. Hard, Imogene Sevin Rodgers, Karl P. Baetcke, William L. Richards, Robert E. Mcgaughy, Lawrence R. ValcovicAbstract:This review paper examines the relationship between chemicals inducing excessive accumulation of alpha 2u-globulin (alpha 2u-g) (CIGA) in hyaline droplets in male rat kidneys and the subsequent development of nephrotoxicity and Renal Tubule neoplasia in the male rat. This dose-responsive hyaline droplet accumulation distinguishes CIGA carcinogens from classical Renal carcinogens. CIGA carcinogens also do not appear to react with DNA and are generally negative in short-term tests for genotoxicity, CIGA or their metabolites bind specifically, but reversibly, to male rat alpha 2u-g. The resulting complex appears to be more resistant to hydrolytic degradation in the proximal Tubule than native, unbound alpha 2u-g. Single cell necrosis of the Tubule epithelium, with associated granular cast formation and papillary mineralization, is followed by sustained regenerative Tubule cell proliferation, foci of Tubule hyperplasia in the convoluted proximal Tubules, and Renal Tubule tumors. Although structurally similar proteins have been detected in other species, including humans, Renal lesions characteristic of alpha 2u-g nephropathy have not been observed. Epidemiologic investigation has not specifically examined the CIGA hypothesis for humans. Based on cancer bioassays, hormone manipulation studies, investigations in an alpha 2u-g-deficient strain of rat, and other laboratory data, an increased proliferative response caused by chemically induced cytotoxicity appears to play a role in the development of Renal Tubule tumors in male rats. Thus, it is reasonable to suggest that the Renal effects induced in male rats by chemicals causing alpha 2u-g accumulation are unlikely to occur in humans.
Akira Saito - One of the best experts on this subject based on the ideXlab platform.
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transcellular water transport and stability of expression in aquaporin 1 transfected llc pk1 cells in the development of a portable bioartificial Renal Tubule device
Tissue Engineering, 2004Co-Authors: Yuji Fujita, Masuo Terashima, Takatosi Kakuta, Johbu Itoh, Takayuki Tokimasa, Dennis Brown, Akira SaitoAbstract:We investigated a portable bioartificial Renal Tubule device (BRTD) consisting of Renal Tubule cells and hollow fibers, to improve the quality of life of patients. It is necessary for a BRTD system to be compact. A compact portable BRTB requires transfection of an appropriate water channel or electrical pump genes in tubular epithelial cells, which should be based on physiological similarities to human kidney function. LLC-PK 1 cells, into which rat kidney aquaporin 1 (AQP1) cDNA was stably transfected, were evaluated for water transport ability. The expression and localization of water AQP1 were examined by Western blotting, RT-PCR, and immunofluorescence. To measure transcellular water permeation, a simple method was applied, using phenol red as a cell-impermeant marker of concentration. In contrast to wild-type LLC-PK1 cells, rat AQP1-transfected cells had high transcellular osmotic water permeability. The expression of rat AQP1 mRNA (ratio of AQP1 to β-actin mRNA) and protein bands (a 28-kDa band and ...
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evaluation of na active transport and morphological changes for bioartificial Renal Tubule cell device using madin darby canine kidney cells
Tissue Engineering, 2002Co-Authors: Yuji Fujita, Takatosi Kakuta, Johbu Itoh, Takayuki Tokimasa, Manabu Asano, Kou Sakabe, Akira SaitoAbstract:The function of current hemodialysis as an artificial kidney is insufficient because of the lack of reabsorptive function. In this study, we intend to develop a bioartificial Renal Tubule cell device (RTD) using tubular epithelial cells and artificial membranes and to evaluate the reabsorptive function of the confluent layers. Madin-Darby canine kidney (MDCK) cells were cultured on a nucleopore polycarbonate membrane for up to 4 weeks after confluence to examine the influence of the culture period on their ability to transport Na+ actively using Na+/K+ATPase (NKA). The results were (1) active Na+ transport of the cells averaged 24.8 mM/m2 ⋅ 24 h during the initial 2 weeks after confluence and then decreased to about 4.2 mM/m2 ⋅ 24 h during the next 2 weeks; (2) NKA localized on the basal-lateral sides of the cells during the initial 2 weeks, whereas it also localized on the apical side of the cells during the next 2 weeks; (3) long-term culture resulted in an increased number of upheaving cell mass, incre...
Huiyao Lan - One of the best experts on this subject based on the ideXlab platform.
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gsdme mediated pyroptosis promotes inflammation and fibrosis in obstructive nephropathy
Cell Death & Differentiation, 2021Co-Authors: Ying Yuan, Zhongxing Huang, Hui Chen, Ruilong Lan, Zeng Wang, Kunmei Lai, Hong Chen, Zhimin Chen, Zhenhuan Zou, Huiyao LanAbstract:Renal tubular cell (RTC) death and inflammation contribute to the progression of obstructive nephropathy, but its underlying mechanisms have not been fully elucidated. Here, we showed that Gasdermin E (GSDME) expression level and GSDME-N domain generation determined the RTC fate response to TNFα under the condition of oxygen-glucose-serum deprivation. Deletion of Caspase-3 (Casp3) or Gsdme alleviated Renal Tubule damage and inflammation and finally prevented the development of hydronephrosis and kidney fibrosis after ureteral obstruction. Using bone marrow transplantation and cell type-specific Casp3 knockout mice, we demonstrated that Casp3/GSDME-mediated pyroptosis in Renal parenchymal cells, but not in hematopoietic cells, played predominant roles in this process. We further showed that HMGB1 released from pyroptotic RTCs amplified inflammatory responses, which critically contributed to Renal fibrogenesis. Specific deletion of Hmgb1 in RTCs alleviated caspase11 and IL-1β activation in macrophages. Collectively, our results uncovered that TNFα/Casp3/GSDME-mediated pyroptosis is responsible for the initiation of ureteral obstruction-induced Renal Tubule injury, which subsequentially contributes to the late-stage progression of hydronephrosis, inflammation, and fibrosis. This novel mechanism will provide valuable therapeutic insights for the treatment of obstructive nephropathy.
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Renal Tubule injury a driving force toward chronic kidney disease
Kidney International, 2018Co-Authors: Bicheng Liu, Taotao Tang, Huiyao LanAbstract:Renal Tubules are the major component of the kidney and are vulnerable to a variety of injuries including hypoxia, proteinuria, toxins, metabolic disorders, and senescence. It has long been believed that Tubules are the victim of injury. In this review, we shift this concept to Renal Tubules as a driving force in the progression of kidney diseases. In response to injury, tubular epithelial cells undergo changes and function as inflammatory and fibrogenic cells, with the consequent production of various bioactive molecules that drive interstitial inflammation and fibrosis. Innate immune-sensing receptors on the tubular epithelium also aggravate immune responses. Necroinflammation, an autoamplification loop between tubular cell death and interstitial inflammation, leads to the exacerbation of Renal injury. Furthermore, tubular cells also play an active role in progressive Renal injury via emerging mechanisms associated with a partial epithelial-mesenchymal transition, cell-cycle arrest at both G1/S and G2/M check points, and metabolic disorder. Thus, a better understanding the mechanisms by which tubular injury drives inflammation and fibrosis is necessary for the development of therapeutics to halt the progression of chronic kidney disease.
G T Nagami - One of the best experts on this subject based on the ideXlab platform.
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sulfur containing amino acids decrease cisplatin cytotoxicity and uptake in Renal Tubule epithelial cell lines
Cancer Chemotherapy and Pharmacology, 2000Co-Authors: R Kroning, A K Lichtenstein, G T NagamiAbstract:Purpose: Nephrotoxicity is one of the major dose-limiting side-effects of cisplatin (DDP). The disproportionate accumulation of cisplatin in kidney tissue may play an important role; however, therapeutic measures to prevent this prime cause of nephrotoxicity are not available. Because certain amino acids (AAs) have been reported to modulate DDP nephrotoxicity in vivo, we explored the potential of all 20 protein AAs, N-acetylcysteine and DL-homocysteine to reduce DDP cytotoxicity and uptake in S1, S3 (proximal Tubule), and DCT (distal convoluted Tubule) cell lines. Methods: Immortalized but non-transformed Renal Tubule epithelial cell lines, derived from specific portions of the nephron of an SV40 transgenic mouse, were grown to confluency and exposed to various concentrations of DDP for 1 h with or without concurrent exposure to AAs in an otherwise AA-free Krebs-Ringer buffer (KRB). After 1 h, cell layers were washed and replenished with medium for cytotoxicity assays, or processed immediately for the determination of DDP accumulation. Cytotoxicity was assessed 48 h later by an MTT assay, and DDP uptake after 1 h was determined by atomic absorption spectroscopy. Results: In an initial screening where the cells were concurrently incubated with 0.25 mM DDP and 1 mM AA for 1 h in KRB, only cysteine (Cys), methionine (Met), N-acetylcysteine and DL-homocysteine reduced DDP toxicity. This effect was enhanced at 5 mM AA and most potent for Cys, which reduced DDP cytotoxicity by 79 ± 3% in S3 cells, by 78 ± 12.2% in DCT cells, and by 19 ± 3.6% in S1 cells (P < 0.05). Reduction of cytotoxicity was less for Met, DL-homocysteine, and N-acetylcysteine, in decreasing order. All four AAs also inhibited DDP uptake in Renal cells, with Cys as the strongest inhibitor. Inhibition of DDP accumulation by 1 mM Cys after 1 h was 39% in S3 cells, 38% in DCT cells, and 28% in S1 cells. Again, reduction of uptake was less for the three other AAs. Pre-complexing of DDP with Cys for 16 h increased its uptake by 8- to 30-fold compared with native DDP, but markedly inhibited its toxicity. Thus, pre-complexing of DDP with Cys could not explain the reduced uptake of DDP, but could partly account for the reduction in cytotoxicity. Double-reciprocal Lineweaver-Burk plots of DDP concentration-versus-uptake rates at a constant concentration of Cys suggested that Cys competitively inhibited DDP uptake in S1 and DCT cells, and in a more complex fashion in S3 cells. Conclusions: We conclude that Cys, Met, N-acetylcysteine, and DL-homocysteine differentially inhibit DDP toxicity and uptake in cultured S1, S3, and DCT cells, and that the inhibition of uptake, as well as the complexation of DDP with Cys within the cell, may prevent toxicity. The structural element R-CH(NH2)-[CH2]1–2-S-R, which is common to all four molecules, may play a crucial role in blocking the transport of DDP, and could have future clinical applications.
Jing Zhang - One of the best experts on this subject based on the ideXlab platform.
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effects of mesenteric lymph duct ligation on apoptosis of Renal Tubule epithelial cells in rats after two hits
Chinese critical care medicine, 2007Co-Authors: Zigang Zhao, Chunyu Niu, Jing ZhangAbstract:OBJECTIVE To explore the effect of mesenteric lymph duct ligation in preventing apoptosis of Renal Tubule epithelial cells in rats by two-hits including hemorrhage and lipopolysaccharide (LPS) challenge. METHODS Forty-five Wistar rats were randomly divided into three groups: the ligation group, the non-ligation group and sham operation group. The two-hits model was established by withdrawing the blood via the right side carotid artery of rats and intragastric administration 4 mg/kg LPS 6 hours after hemorrhage, and mesenteric lymph flow was blocked by ligating mesenteric lymph duct in ligation group. Twenty-four hours after operation, kidney was harvested for pathological examination, and the apoptosis cells rate of Renal Tubule epithelial cells were determined by method of terminal-deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL), the expression of apoptosis-correlating gene bcl-2 and bax protein were determined by streptavidin-biotin complex (SABC) immunohistochemical method. RESULTS After two-hits, the apoptosis rate and expression of bax protein of Renal Tubule epithelial cells in non-ligation group were significantly increased, and expression of bcl-2 protein was significantly lower as compared with those of sham operation group (all P<0.01). But the apoptosis rate and expression of bax protein of Renal Tubule epithelial cells in ligation group were significantly lower, and expression of bcl-2 protein was significantly increased as compared with non-ligation group (all P<0.01). CONCLUSION The results demonstrate that the ligation of mesenteric lymph duct could ameliorate the apoptosis of Renal Tubule epithelial cells in rats as produced by hemorrhage and LPS, and its mechanism might relate to the reduction of the down regulation of gene expression of bax protein and enhancement of the expression of bcl-2 protein after ligation of mesenteric lymph duct.
