Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P41181 (collecting duct)
 5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal clear cell tubules and clear/acidophilic cell tumors were induced in male Sprague-Dawley rats by 7 weeks oral administration (stop model) of N-nitrosomorpholine (NNM) at a concentration of 12 mg/100 ml in the drinking water. Twelve, 23 and 34 weeks after withdrawal of NNM serial cryostat sections of the kidneys were histochemically analyzed for the following parameters: glucose transporter proteins (GLUT1, GLUT2), glycogen content and the activities of glycogen synthase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphatase (G6Pase), glucose-6-phosphate dehydrogenase (G6PDH), hexokinase (HK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase (PK), succinate dehydrogenase (SDH), malate dehydrogenase (MDH), alkaline phosphatase (ALP), acid phosphatase (ACP) and gamma-glutamyltransferase (GGT). Clear cell (glycogenotic) tubules first appeared at 23 weeks, and clear/acidophilic cell tumors at 34 weeks after withdrawal of the carcinogen. G6Pase, ALP, GGT and GLUT2 were absent in clear cell tubules, clear/acidophilic cell tubules, and clear/acidophilic cell tumors indicating a sequential origin of all these types of lesions from the collecting duct system, in line with previous morphological findings. In comparison to the collecting duct epithelium, glycogenotic tubules demonstrated an increased activity of PHO and reduced activities of glycolytic and mitochondrial enzymes, which were accompanied by a strongly reduced expression of GLUT1. Moderately increased activities of glycolytic and mitochondrial enzymes were observed in the clear cells of clear/acidophilic cell tubules and tumors compared with those in glycogenotic tubules. They had slightly increased activities of the glycolytic enzymes GAPDH and PK compared with normal collecting duct epithelium, while most of them were nearly lacking in GLUT1. Our findings suggest that glycogen storage is not due to an increased uptake of glucose from the blood, but results from a disturbance in intracellular flux of metabolites. The development of clear cell tubules from the normal collecting duct epithelium is accompanied by a markedly decreased expression of GLUT1 along with a reduction in glycolytic and mitochondrial enzymes. This reduction of enzyme activities is replaced by an increase in enzyme activities in clear/acidophilic cell tumors indicating a fundamental shift in carbohydrate metabolism during progression from preneoplastic to neoplastic lesions.
Carcinogenesis 1992 Dec
PMID:Sequential changes in glycogen content, expression of glucose transporters and enzymic patterns during development of clear/acidophilic cell tumors in rat kidney. 147 41

Besides erythroleukemias and sarcomas, avian erythroblastosis virus strain ES4 (AEV-ES4) induces renal adenocarcinomas (RCas) in chickens. To search for the cells of origin and the mechanism of the development of RCas, we investigated the RCas produced by td359AEV, a mutant of AEV-ES4 which lacks a leukemogenic effect, but which is sarcomagenic. Spindle cell sarcomas in various organs and RCas developed in a high number of chickens inoculated with td359AEV. RCas were tubulo-cystopapillary structures of basophilic cells and originated only from differentiated principal cells (PCs) of the renal collecting duct system. The origin of tumors from PCs was indicated by connections of tumor epithelium to segments of the collecting duct system, including connecting tubules and cortical and medullary collecting ducts. Tumor cells showed typical mucopolysaccharide-containing vacuoles which are characteristic of chicken PCs. Viral particles were observed throughout the kidney. Moreover, the highest numbers of particles as well as budding-images of them were seen (apart from tumor cells) in podocytes and distal tubule cells which did not undergo neoplastic change. The susceptibility of PCs to undergo neoplastic transformation could not be related to a particular activation state of the erbB gene, in view of the fact that cerbB expression was detected by in situ hybridization in the epithelium lining the Bowmann's capsule and the entire renal tubule system. From data of Northern blot and in situ hybridization techniques, it was suggested that the neoplastic transformation of PCs was elicited by overexpression of the v-erbB oncogene, a feature of tumor cells already detected in renal tubules lined by basophilic proliferating cells, the first stages of renal carcinogenesis induced by td359AEV. According to Southern blot analysis, td359AEV proviruses were randomly inserted in tumor DNAs and the RCas were polyclonal in nature.
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PMID:Cellular and molecular mechanisms of renal carcinogenesis induced by avian erythroblastosis virus. 173 53

It is now apparent that multiple genetic alterations, including oncogene activation and tumor suppressor gene inactivation, are necessary steps in carcinogenesis. We have studied this concept in renal cancers by looking at specific tumor suppressor genes implicated in several allelotyping studies. Primary, predominantly low stage renal tumors of varying grades and histologic subtypes were investigated for allelic loss of 3p, 17p and the p53 gene, the DCC gene and the Rb gene and its product. 3p loss occurred in 47% of tumors studied and was much more common in clear cell cancers (85%). 17p and p53 gene loss were relatively uncommon events with only 6 of 42 tumors demonstrating loss. None of the tumors with typical histologies had allelic loss of the DCC gene, though loss did occur in leiomyosarcoma and a collecting duct tumor. Allelic loss of the Rb gene occurred in one clear cell tumor, the leiomyosarcoma, and, interestingly, in both collecting duct tumors in this series. Allelic loss of the Rb gene was correlated with little or no RB protein expression as judged by immunohistochemistry. At all loci studied, allelic loss did not appear to correlate with tumor grade or stage. These results suggest that inactivation of the p53, Rb, and DCC genes by allelic loss are uncommon events in the early stages of renal carcinogenesis.
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PMID:Tumor suppressor gene allelic loss in human renal cancers. 837 15

Carbonic anhydrase isozyme XII (CA XII) is a novel membrane-associated protein with a potential role in von Hippel-Lindau carcinogenesis. Although Northern blotting has revealed positive signal for CA XII in normal human kidney, this is the first study to demonstrate its cellular and subcellular localization along the human nephron and collecting duct. Immunohistochemistry with a polyclonal antibody (PAb) raised against truncated CA XII revealed distinct staining in the basolateral plasma membrane of the epithelial cells in the thick ascending limb of Henle and distal convoluted tubules, and in the principal cells of the collecting ducts. A weak basolateral signal was also detected in the epithelium of the proximal convoluted tubules. In addition to the normal kidney specimens, this immunohistochemical study included 31 renal tumors. CA XII showed moderate or strong plasma membrane-associated expression in most oncocytomas and clear-cell carcinomas. The segmental, cellular, and subcellular distribution of CA XII along the human nephron and collecting duct suggests that it may be one of the key enzymes involved in normal renal physiology, particularly in the regulation of water homeostasis. High expression of CA XII in some renal carcinomas may contribute to its role in von Hippel-Lindau carcinogenesis.
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PMID:Expression of the membrane-associated carbonic anhydrase isozyme XII in the human kidney and renal tumors. 1110 28

A mechanism decreasing oxidative metabolism during normal cell division and growth is expected to direct substrates toward biosyntheses rather than toward complete oxidation to CO(2). Hence, any event decreasing oxidative phosphorylations (OXPHOS) could provide a proliferating advantage to a transformed or tumor cell in an oxidative tissue. To test this hypothesis, we studied mitochondrial enzymes, DNA and OXPHOS protein content in three types of renal tumors from 25 patients. Renal cell carcinomas (RCCs) of clear cell type (CCRCCs) originate from the proximal tubule and are most aggressive. Chromophilic RCCs, from similar proximal origin, are less aggressive. The benign renal oncocytomas originate from collecting duct cells. Mitochondrial enzyme and DNA contents in all tumor types or grades differed significantly from normal tissue. Mitochondrial impairment increased from the less aggressive to the most aggressive RCCs, and correlated with a considerably decreased content of OXPHOS complexes (complexes II, III, and IV of the respiratory chain, and ATPase/ATP synthase) rather than to the mitochondrial content (citrate synthase and mitochondrial (mt)DNA). In benign oncocytoma, some mitochondrial parameters (mtDNA, citrate synthase, and complex IV) were increased 4- to 7-fold, and some were slightly increased by a factor of 2 (complex V) or close to normal (complexes II and III). A low content of complex V protein was found in all CCRCC and chromophilic tumors studied. However F(1)-ATPase activity was not consistently decreased and its impairment was associated with increased aggressiveness in CCRCCs. Immunodetection of free F(1)-sector of complex V demonstrated a disturbed assembly/stability of complex V in several CCRCC and chromophilic tumors. All results are in agreement with the hypothesis that a decreased OXPHOS capacity favors faster growth or increased invasiveness.
Carcinogenesis 2002 May
PMID:Low mitochondrial respiratory chain content correlates with tumor aggressiveness in renal cell carcinoma. 1201 48

Hydrochlorothiazide is a diuretic active at the distal convoluted tubule and collecting duct. Toxicology and carcinogenesis studies were conducted by feeding diets containing hydrochlorothiazide (USP grade, greater than 98% pure) to groups of F344/N rats and B6C3F1 mice of each sex for 15 days, 13 weeks, 1 year, or 2 years. Additional studies were performed to evaluate teratologic effects in CD(R). rats and CD(R).-1 mice. Genetic toxicology studies were performed with Salmonella, Chinese hamster ovary (CHO) cells, mouse lymphoma cells, and Drosophila. Fifteen-Day and Thirteen-Week Studies: All rats and mice lived to the end of the 15-day studies (dietary concentrations of 0 and 3,125-50,000 ppm). The final mean body weights of all dosed rat groups were 5%-11% lower than those of controls. The final mean body weights of the groups of male mice that received 6,250-50,000 ppm were 10%-14% lower than that of controls. The final mean body weights of dosed and control female mice were similar. Calculi were seen in the urinary bladder of 2/5 male and 2/5 female mice at 50,000 ppm and in 1/5 male and 1/5 female mice at 25,000 ppm. All rats lived to the end of the first 13-week studies (dietary concentrations of 0 and 3,125-50,000 ppm). Final body weights of dosed rats were 7%-16% lower than those of controls. Mineralization in the kidney was observed in all dosed rats and because of this, additional 13-week studies in rats were conducted at lower dietary concentrations. All rats lived to the end of the second 13-week studies (dietary concentrations of 0 and 250-4,000 ppm). The final mean body weights of all dosed rat groups were 5%-10% lower than those of controls. Renal mineralization was dose related and judged to be minimal to mild at the lowest dose. In the 13-week studies in mice, 7/10 males and 1/10 females that received 50,000 ppm hydrochlorothiazide died. The final mean body weights of mice that received 50,000 ppm were 11% lower than those of controls for males and females. Calculi were seen in the urinary bladder of mice that received hydrochlorothiazide at 12,500 ppm and above. Nephrosis occurred with dose-related incidences in mice receiving 12,500 ppm and above. Based on these results, 2-year studies were conducted by feeding diets containing 0, 250, 500, or 2,000 ppm hydrochlorothiazide to groups of 50 male and 50 female rats for 105-106 weeks. Diets containing 0, 2,500, or 5,000 ppm hydrochlorothiazide were fed to groups of 50 male and 50 female mice for 103-104 weeks. Ten additional rats per sex and dose group were placed on study and killed at 1 year for blood-clotting studies and histopathologic examination. Effects in the One-Year Studies: One of 10 female rats in the 1-year study group that received 2,000 ppm died with internal hemorrhage. In addition, evidence of hemorrhage was found in 11 of the 16 dosed female rats that died during the first year of the 2-year study. Hematologic analyses revealed no compound-related effects; however, activated partial thromboplastin times (APTTs) were highly variable and were lengthened in some dosed male rats. No effects on APTTs were seen for females, and no effects on prothrombin times or on the fibrinogen content of plasma were observed for dosed male or female rats. Nephropathy occurred in dosed and control rats, and the severity was judged to be greater in dosed male and high dose female rats. Increased incidences of mild focal renal mineralization were also seen in mid and high dose male rats and dosed female rats. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were 8%-25% lower than those of controls. Mean body weights of dosed and control mice were similar throughout the studies. No significant differences in survival were observed between rats or mice of either sex (rats-- male: control, 18/50; low dose, 16/50; mid dose, 9/50; high dose, 11/50; female: 31/50; 26/50; 30/50; 27/50; mice--male: control, 43/50; low dose, 42/50; high dose, 43/50; female: 38/50; 40/50; 35/50). Survival of all groups of male rats was low because a lar female: 38/50; 40/50; 35/50). Survival of all groups of male rats was low because a large number of animals were killed in a moribund condition late in the study. The average daily feed consumption by dosed rats was 89%-94% that by controls. The average amount of hydrochlorothiazide consumed per day was approximately 11, 23, or 89 mg/kg for low, mid, or high dose rats. The average daily feed consumption by dosed mice was 100%-105% that by controls. The average amount of hydrochlorothiazide consumed per day was approximately 280 or 575 mg/kg for low dose or high dose mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nephropathy occurred in nearly all male and female rats, but the severity of this disease was greater in dosed rats, as evidenced by increases in renal cysts and epithelial hyperplasia of the renal pelvis in dosed rats shown in the following table (see page 4 of the Technical Report). Mineralization was observed at increased incidences in dosed male and dosed female rats. Changes associated with or secondary to renal injury were increased in dosed rats. These lesions included parathyroid hyperplasia, fibrous osteodystrophy of bone, and mineralization of multiple organs. Adenomas or carcinomas (combined) of the Zymbal gland in male rats occurred in 1/50 control, 1/49 low dose, 2/50 mid dose, and 4/50 high dose animals. The historical incidence of Zymbal gland neoplasms in untreated F344/N rats is 19/1,936 (1.0%), and the highest observed control group incidence is 4/50. This marginal increase was not considered to be chemically related. The incidences of fibroadenomas of the mammary gland were decreased in dosed female rats (30/50; 12/50; 11/49; 5/50). The incidence of hepatocellular neoplasms was increased in high dose male mice (adenomas or carcinomas, combined: control, 7/48; low dose, 10/49; high dose, 21/50). The historical incidence of hepatocellular adenomas or carcinomas (combined) is 609/2,032 (30%) in untreated controls. Teratology: Hydrochlorothiazide produced no teratologic effects in the offspring of CD®. rats or CD®.-1 mice after gavage administration to pregnant females on day 6 through day 15 of gestation. Genetic Toxicology: In the absence of exogenous metabolic activation, hydrochlorothiazide produced an equivocal increase in revertant colonies in Salmonella typhimurium strain TA98; no increase was observed in strains TA100, TA1535, or TA1537 with or without activation. Hydrochlorothiazide induced an increase in trifluorothymidine (Tft)-resistant cells in a mouse lymphoma L5178Y/TK+/- assay without exogenous metabolic activation; this assay was not performed with activation. In cultured CHO cells, hydrochlorothiazide induced sister chromatid exchanges (SCEs) in the presence and absence of exogenous metabolic activation but did not induce chromosomal aberrations. Hydrochlorothiazide did not increase the frequency of sex-linked recessive lethal mutations when administered by feeding or injection to adult male Drosophila melanogaster. Audit: The data, documents, and pathology materials from the 2-year studies of hydrochlorothiazide have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of hydrochlorothiazide for male or female F344/N rats given feed containing 250, 500, or 2,000 ppm hydrochlorothiazide. There was equivocal evidence of carcinogenic activity of hydrochlorothiazide for male B6C3F1 mice, based on increased incidences of hepatocellular neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice given diets containing 2,500 or 5,000 ppm hydrochlorothiazide. Chronic renal disease was more severe in rats administered hydrochlorothiazide, and increased incidences of secondary lesions (parathyroid hyperplasia, fibrous osteodystrophy, and mineralization in multiple organs) occurred in dosed rats. Synonym: 6-chloro-3,4-dihydro-2H-1,2,4-benzothia-diazine-7-sulfonamide 1,1-dioxide Trade Names: Aquarius; Bremil; Chlorzide; Cidrex; Dichlorosal; Dichlotride; Diclotride; Direma; Disalunil; Esidrix; Fluvin; Hidroronol; Hydril; Hydro-Aquil; Hydro-Diuril; Hydrosaluric; Hydrothide; Hypothiazide; Ivaugan; Jen-Diril; Maschitt; Nefrix; Neo-Codema; Neoflumen; Oretic; Panurin; Ro-Hydrazide; Thiaretic; Thiuretic; Urodiazin; Vetidrex
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PMID:Toxicology and Carcinogenesis Studies of Hydrochlorothiazide (CAS No. 58-93-5) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1269 84

To elucidate the relationship between tumor genesis and the mitochondrial energy metabolism in renal neoplasms, we studied three individual enzyme activities of the oxidative phosphorylation, two components of the Krebs cycle and the mitochondrial DNA content of renal carcinomas including 29 conventional, five papillary, two unclassified carcinomas with sarcomatoid features and one collecting duct carcinoma. A significant reduction of all mitochondrial enzyme activities including complex V, as well as of the mitochondrial DNA content was detected in 34 of 37 renal carcinoma tissues as compared with control kidney. Mitochondrial enzyme activities and mitochondrial DNA levels were not statistically different between the conventional, papillary and unclassified sarcomatoid type of renal carcinoma and did not correlate with tumour grade, metastasis, ploidy and proliferative activity as determined by Ki-67 staining. Taken together, our data indicate that a co-ordinated down-regulation of all components necessary for mitochondrial energy metabolism occurs in most renal carcinomas as an early event in carcinoma formation, which does not change with progression of the disease.
Carcinogenesis 2004 Jun
PMID:Decrease of mitochondrial DNA content and energy metabolism in renal cell carcinoma. 1476 59

The fragile histidine triad (FHIT) gene located in human chromosome 3p14.2 is a candidate tumor suppressor gene that has a diadenosine triphosphate (Ap3A) hydrolase activity, but its role in carcinogenesis remains uncertain. To investigate the role of FHIT in normal cells, specific polyclonal antibodies to recombinant rat FHIT protein were generated. Immunoblot analysis revealed the 17-kd FHIT protein was most abundantly expressed in kidney and liver, whereas heart, skeletal muscle, and adrenal gland expressed trace amounts. In kidney, immunohistochemical staining was strongly observed in distal convoluted tubule and collecting duct during postnatal growth period. By a nested reverse transcription-PCR analysis of FHIT from 2 human kidney cancer cell lines, four abnormal-sized FHIT transcripts, with deletion and/or insertion, were detected. These were derived from the results of exon skipping, and/or insertion of FHIT intron 5 sequence, or selection of cryptic splice site within the FHIT cDNA sequence 179-180. Taken together, our data indicate that FHIT expression is frequently altered in human kidney cancer cell lines by alternative splicing, and suggest that the FHIT protein may play a pivotal role in regulating intracellular metabolism of the distal convoluted tubule and collecting duct in maturity.
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PMID:Expression of the fragile histidine triad gene in normal rat tissues and human kidney cancer cell lines. 1508 May 5

Chromophobe renal cell carcinoma (RCC) and collecting duct carcinoma (CDC) are derived from the collecting duct epithelia, although their morphology, molecular biologic characteristics and clinical behaviors are quite different. Herein is presented a case of RCC possessing the chromophobe RCC and CDC elements occurring in a 64 year-old Japanese woman. The patient was referred to Yokohama City University Hospital with complaints of persistent back pain and fever. Radiologic examinations revealed a left renal tumor, and radical nephrectomy was performed. The patient died with multiple metastases, 8 months after the operation. The resected tumor showed an invasive growth, and its cut surface was heterogenous with hemorrhage and necrosis. Histologically, the tumor was composed of chromophobe elements with dedifferentiation, and CDC elements. The chromophobe and CDC elements had obvious histological transition. Lectin histochemistry and immunohistochemistry confirmed that this tumor was derived from the distal nephron. c-KIT, p53 and Ki67 antigen showed differential localization between the chromophobe and CDC elements, even in the transitional areas. Along with the previous reports, the present case seemed to be composite RCC derived from the collecting duct, which might present clues to elucidate carcinogenesis in the distal nephron.
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PMID:Composite distal nephron-derived renal cell carcinoma with chromophobe and collecting duct carcinomatous elements. 1594 94

The association between human papillomavirus (HPV) infection and carcinogenesis has long been established in literature, with the strongest evidence for its role in cervical carcinoma. The role of HPV in urological tumors has been investigated and sporadic reports have linked HPV infection to bladder, prostate, renal, penile, and testicular cancer. Although less rigorously studied, there are a few conflicting results about the role of HPV in the development of malignant renal tumors. Moreover, no data are available for association of HPV DNA and expression of P16 in benign renal tumors. Formalin-fixed, paraffin-embedded tissues from 62 renal tumors (40 clear cell, 9 papillary, and 3 chromophobe renal cell carcinomas, 1 collecting duct carcinoma, 2 urothelial carcinoma of renal pelvis and 7 oncocytomas) were immunostained with low-risk and high-risk HPV DNA (6, 11, 16, 18, 31, 33, 42, 51, 52, 56, 58). Tissue microarray sections of 62 tumors were stained with P16 by immunohistochemistry. Signal amplified colorimetric in situ hybridization was performed on microarray sections using biotinylated probes for HPV subtypes 6, 11, 16, 18. A nuclear dot-like signal was considered positive for low-risk and high-risk HPV by immunohistochemistry and in situ hybridization and nuclear or cytoplasmic staining is considered positive for P16. No staining for HPV DNA and P16 was found in any type of renal tumors. Our results support that HPV does not seem to play a role in the development of benign and malignant renal tumors.
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PMID:Human Papillomavirus DNA and P16INK4A are not detected in renal tumors with immunohistochemistry and signal-amplified in situ hybridization in paraffin-embedded tissue. 1712 41


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