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

Experimental nephrotic syndrome results in sodium retention, reflecting, at least in part, an intrinsic defect in renal sodium handling in the distal nephron. We studied the relationships among plasma atrial natriuretic peptide (ANP) concentration, sodium excretion (UNaV), and urinary cyclic GMP excretion (UcGMPV) in vivo, and the responsiveness of isolated glomeruli and inner medullary collecting duct (IMCD) cells to ANP in vitro, in rats with adriamycin nephrosis (6-7 mg/kg body weight, intravenously). 3-5 wk after injection, rats were proteinuric and had a blunted natriuretic response to intravenous infusion of isotonic saline, 2% body weight given over 5 min. 30 min after onset of the infusion, plasma ANP concentrations were elevated in normals and were even higher in nephrotics. Despite this, nephrotic animals had a reduced rate of UcGMPV after the saline infusion, and accumulation of cGMP by isolated glomeruli and IMCD cells from nephrotic rats after incubation with ANP was significantly reduced compared to normals. This difference was not related to differences in binding of 125I-ANP to IMCD cells, but was abolished when cGMP accumulation was measured in the presence of 10(-3) M isobutylmethylxanthine or zaprinast (M&B 22,948), two different inhibitors of cyclic nucleotide phosphodiesterases (PDEs). Infusion of zaprinast (10 micrograms/min) into one renal artery of nephrotic rats normalized both the natriuretic response to volume expansion and the increase in UcGMPV from the infused, but not the contralateral, kidney. These results show that, in adriamycin nephrosis, blunted volume expansion natriuresis is associated with renal resistance to ANP, demonstrated both in vivo and in target tissues in vitro. The resistance does not appear related to a defect in binding of the peptide, but is blocked by PDE inhibitors, suggesting that enhanced cGMP-PDE activity may account for resistance to the natriuretic actions of ANP observed in vivo. This defect may represent the intrinsic sodium transport abnormality linked to sodium retention in nephrotic syndrome.
 ...
PMID:Cellular basis for blunted volume expansion natriuresis in experimental nephrotic syndrome. 132 96

The aquaporins are molecular water channels that mediate transcellular water transport across water-permeable epithelia. To investigate the cause of the concentrating defect in the nephrotic syndrome, immunoblotting using membrane fractions from inner medulla was utilized to assess the level of expression of four aquaporin water channels in vehicle-treated versus puromycin aminonucleoside (PAN)-treated rats. Scanning electron microscopy demonstrating loss of glomerular foot processes and measurements of urinary protein excretion confirmed the efficacy of the PAN treatment. In rats receiving PAN, there was an increase in plasma vasopressin, without a change in plasma sodium concentration. Inner medullary tissue hypertonicity was sustained in PAN-treated rats while the urinary osmolality was low, pointing to defective osmotic equilibration across the collecting ducts in PAN-nephrosis. Among collecting duct aquaporins, there was an 87% decrease in aquaporin-2 expression and a 70% decrease in aquaporin-3 expression in the inner medulla, whereas aquaporin-4 expression was unaltered. Transmission electron microscopy of the inner medullary collecting ducts of PAN-treated rats showed normal-appearing cells. Thus, PAN-nephrosis is associated with an extensive downregulation of collecting duct water channel expression despite increased circulating vasopressin, providing an explanation for the concentrating defect associated with the nephrotic syndrome.
 ...
PMID:Reduced renal medullary water channel expression in puromycin aminonucleoside--induced nephrotic syndrome. 901 44

Renal cystic disease include heritable, developmental and acquired disorders. Morphological features were extensively studied mainly in cases of autosomal dominant polycystic and experimentally induced cystic disorders. We report the immunohistochemical (cytokeratin, epithelial membrane antigen, vimentin, Tamm-Horsfall protein, proliferating cell nuclear antigen) and lectin-binding (soybean agglutinin, Dolichos biflorus agglutinin) profile of cystic kidneys from 9 surgically removed and 21 autopsy cases. The primary renal diseases displayed great diversity. Beside polycystic kidney diseases we studied cysts associated to renal neoplasm, hemodialysis, nephrosis syndrome and chronic transplant rejection. Cystic epithelium demonstrated positive reactions with distal tubular markers (epithelial membrane antigen, cytokeratin) or collecting duct (soybean agglutinin, Dolichos biflorus agglutinin) and Henle loop markers (Tamm-Horsfall protein) but the latter in lesser extent. The large number of the vimentin positive cases are suggestive to dedifferentiation or cellular regeneration. The former might be underlined by the diffuse cytoplasmic or basolateral membrane staining of the epithelial membrane antigen in some cystic epithelial cells. Not the cystic epithelium but rather the neighbouring non-dilated tubular cells and interstitial cells presented proliferative activity which was most intense in areas where vimentin and variable nephron segment markers in the same tissue were expressed. Positive reaction of the type IV basement membrane collagen and the rate of the inflammation failed to show similar connection. This finding suggests the importance of the inflammatory cells in the development and/or expansion of the cysts.
 ...
PMID:Morphology of cystic renal lesions. Lectin and immuno-histochemical study. 940 36

Renal sodium retention is responsible for ascites and edema in nephrotic syndrome. In puromycin aminonucleoside (PAN)-induced nephrosis, sodium retention originates in part from the collecting duct, and it is associated with increased Na,K-ATPase activity in the cortical collecting duct (CCD). The aims of this study were to evaluate whether the outer medullary collecting duct (OMCD) also participates to sodium retention and to determine the mechanisms responsible for stimulation of Na,K-ATPase in CCD. PAN nephrosis increased Na,K-ATPase activity in the CCD but not in OMCD. The two-fold increase of Na,K-ATPase activity in CCD was associated with two-fold increases in the number of alpha and beta Na,K-ATPase subunits mRNA determined by quantitative RT-PCR and of the total amount of Na,K-ATPase alpha subunits estimated by Western blotting. PAN nephrosis also increased two-fold the amount of Na,K-ATPase alpha subunit at the basolateral membrane of CCD principal cells, as determined by Western blotting after biotinylation and streptavidin precipitation and by immunofluorescence. The intracellular pool of latent Na,K-ATPase units also increased in size and was no longer recruitable by vasopressin and cAMP. This unresponsiveness of the intracellular pool of Na,K-ATPase to vasopressin was not the result of any alteration of the molecular and functional expression of the vasopressin V(2) receptor/adenylyl cyclase (AC) complex. It is concluded that PAN nephrosis (1) does not alter sodium reabsorption in OMCD, (2) is associated with increased synthesis and membrane expression of Na,K-ATPase in the CCD, and (3) alters the normal trafficking of intracellular Na,K-ATPase units to the basolateral membrane.
 ...
PMID:Increased synthesis and avp unresponsiveness of Na,K-ATPase in collecting duct from nephrotic rats. 1167

Platelet-derived growth factor-C (PDGF-C) is a new member of the PDGF family. Its expression in normal and diseased kidney is unknown. Rabbit antisera were generated against human full-length, core domain, and mouse PDGF-C, and their specificity was confirmed by Western blot analyses. Renal PDGF-C expression was analyzed by immunohistochemistry in normal rats (n = 8), mesangioproliferative anti-Thy 1.1 nephritis (n = 4 each at days 1, 4, 6, and 85), passive Heymann nephritis (PHN, n = 4), puromycin nephrosis (PAN, n = 2), Milan normotensive rats (MN, n = 2), and obese Zucker rats (n = 3). PDGF-C expression was also studied in anti-Thy 1.1 rats treated with PDGF-B aptamer antagonists (n = 5) or irrelevant control aptamers (n = 5). PDGF-C was constitutively expressed in arterial smooth muscle cells and collecting duct epithelial cells. Mesangial PDGF-C was markedly upregulated in anti-Thy 1.1 nephritis in parallel with the peak mesangial cell proliferation. Furthermore, PDGF-CC acted as a potent growth factor for mesangial cells in vitro. Inhibition of PDGF-B via specific aptamers reduced the injury in anti-Thy 1.1 nephritis but did not affect the glomerular PDGF-C overexpression or the mitogenicity of PDGF-CC in vitro. In PHN, PAN, and obese Zucker rats, glomeruli remained negative for PDGF-C despite severe glomerular injury. PDGF-C localized to podocytes at sites of focal and segmental sclerosis in MN. Interstitial PDGF-C expression was increased at sites of fibrosing injury in obese Zucker rats. The use of the different antisera resulted in virtually identical findings. It is concluded that PDGF-C is a novel mesangial cell mitogen that is constitutively expressed in the kidney and specifically upregulated in mesangial, visceral epithelial, and interstitial cells after predominant injury to these cells. PDGF-C may therefore be involved in the pathogenesis of renal scarring.
 ...
PMID:Expression of a novel PDGF isoform, PDGF-C, in normal and diseased rat kidney. 1191 50

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
 ...
PMID:Toxicology and Carcinogenesis Studies of Hydrochlorothiazide (CAS No. 58-93-5) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1269 84

Oedema is a defining element of the nephrotic syndrome. Its' management varies considerably between clinicians, with no national or international clinical guidelines, and hence variable outcomes. Oedema may have serious sequelae such as immobility, skin breakdown and local or systemic infection. Treatment of nephrotic oedema is often of limited efficacy, with frequent side-effects and interactions with other pharmacotherapy. Here, we describe the current paradigms of oedema in nephrosis, including insights into emerging mechanisms such as the role of the abnormal activation of the epithelial sodium channel in the collecting duct. We then discuss the physiological basis for traditional and novel therapies for the treatment of nephrotic oedema. Despite being the cardinal symptom of nephrosis, few clinical studies guide clinicians to the rational use of therapy. This is reflected in the scarcity of publications in this field; it is time to undertake new clinical trials to direct clinical practice.
 ...
PMID:Nephrotic Syndrome: Oedema Formation and Its Treatment With Diuretics. 3069 63