Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0035078 (renal failure)
 31,970 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Lowe syndrome (LS) is a life-threatening, developmental disease characterized by mental retardation, cataracts and renal failure. Although this human illness has been linked to defective function of the phosphatidylinositol 5-phosphatase, Ocrl1 (Oculo-Cerebro-Renal syndrome of Lowe protein 1), the mechanism by which this enzyme deficiency triggers the disease is not clear. Ocrl1 is known to localize mainly to the Golgi apparatus and endosomes, however it translocates to plasma membrane ruffles upon cell stimulation with growth factors. The functional implications of this inducible translocation to the plasma membrane are presently unknown. Here we show that Ocrl1 is required for proper cell migration, spreading and fluid-phase uptake in both established cell lines and human dermal fibroblasts. We found that primary fibroblasts from two patients diagnosed with LS displayed defects in these cellular processes. Importantly, these abnormalities were suppressed by expressing wild-type Ocrl1 but not by a phosphatase-deficient mutant. Interestingly, the homologous human PI-5-phosphatase, Inpp5b, was unable to complement the Ocrl1-dependent cell migration defect. Further, Ocrl1 variants that cannot bind the endocytic adaptor AP2 or clathrin, like Inpp5b, were less apt to rescue the migration phenotype. However, no defect in membrane recruitment of AP2/clathrin or in transferrin endocytosis by patient cells was detected. Collectively, our results suggest that Ocrl1, but not Inpp5b, is involved in ruffle-mediated membrane remodeling. Our results provide new elements for understanding how Ocrl1 deficiency leads to the abnormalities associated with the LS.
 ...
PMID:Lowe syndrome patient fibroblasts display Ocrl1-specific cell migration defects that cannot be rescued by the homologous Inpp5b phosphatase. 1970 Apr 99

Renal tubular reabsorption is important for extracellular fluid homeostasis and much of this occurs via the receptor-mediated endocytic pathway. This pathway is disrupted in Dent's disease, an X-linked renal tubular disorder that is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure. Dent's disease is due to mutations of CLC-5, a chloride/proton antiporter, expressed in endosomes and apical membranes of renal tubules. Loss of CLC-5 function alters receptor-mediated endocytosis and trafficking of megalin and cubilin, although the underlying mechanisms remain to be elucidated. Here, we report that CLC-5 interacts with kinesin family member 3B (KIF3B), a heterotrimeric motor protein that facilitates fast anterograde translocation of membranous organelles. Using yeast two-hybrid, glutathione-S-transferase pull-down and coimmunoprecipitation assays, the COOH terminus of CLC-5 and the coiled-coil and globular domains of KIF3B were shown to interact. This was confirmed in vivo by endogenous coimmunoprecipitation of CLC-5 and KIF3B and codistribution with endosomal markers in mouse kidney fractions. Confocal live cell imaging in kidney cells further demonstrated association of CLC-5 and KIF3B, and transport of CLC-5-containing vesicles along KIF3B microtubules. KIF3B overexpression and underexpression, using siRNA, had reciprocal effects on whole cell chloride current amplitudes, CLC-5 cell surface expression, and endocytosis of albumin and transferrin. Clcn5(Y/-) mouse kidneys and isolated proximal tubular polarized cells showed increased KIF3B expression, whose effects on albumin endocytosis were dependent on CLC-5 expression. Thus, the CLC-5 and KIF3B interaction is important for CLC-5 plasma membrane expression and for facilitating endocytosis and microtubular transport in the kidney.
 ...
PMID:CLC-5 and KIF3B interact to facilitate CLC-5 plasma membrane expression, endocytosis, and microtubular transport: relevance to pathophysiology of Dent's disease. 1994 36

Plasma BNP and NT-proBNP are often regarded as interchangeable parameters in assessing heart failure (HF) severity and prognosis. Renal failure results in disproportionate increases of NT-proBNP and an increased NT-proBNP/BNP ratio. Low kidney function is therefore considered particularly when NT-proBNP is used to assess HF. The purpose of this study was to identify other conditions affecting the NT-proBNP/BNP ratio. We examined the NT-proBNP/BNP ratio, 26 other lab parameters, and clinical factors in 218 patients admitted to the HF ward. In addition to renal function, we also found significant correlations between the NT-proBNP/BNP ratio and inflammation as measured by orosomucoid (r = 0.525, p < 0.0001), CRP (r = 0.333, p < 0.0001), haptoglobulin (r = 0.201, p = 0.02), and alpha1-antitrypsin (r = 0.223, p = 0.01). Reverse correlation was found with transferrin (r = -0.323, p < 0.0001), albumin (r = -0.251, p = 0.003), and S-Fe (r = -0.205, p = 0.02), parameters known to decrease during inflammation. Inflammation increased levels of NT-proBNP more than BNP, resulting in an increased NT-proBNP/BNP ratio. Our findings indicate that NT-proBNP should be evaluated concomitantly with inflammatory status to avoid overestimation of HF severity.
 ...
PMID:Inflammation increases NT-proBNP and the NT-proBNP/BNP ratio. 2022 22

Nephrogenic systemic fibrosis (NSF) is a systemic disorder that occurs in patients with renal failure and manifests as a thickening of the skin and flexion contractures of the joints. The etiology may involve an exposure to a gadolinium (Gd)-based magnetic resonance contrast agent. It has been proposed that in hemodialysis (HD) patients, iron mobilization (decreased total iron-binding capacity, increased iron level, and transferrin oversaturation) causes a transmetallation reaction and the release of free Gd from its chelator with the deposition of both Gd and iron in the affected tissues leading to fibrosis. The objective of this study was to investigate whether the use of gadopentetate dimeglumine leads to iron mobilization and to the development of NSF in HD patients. A retrospective chart analysis of 236 HD patients was performed and patients who had received a Gd-containing contrast agent were selected for analysis of their iron studies before and after the Gd exposure. A total of 25 patients were identified as having had a magnetic resonance imaging study and all were administered gadopentetate dimeglumine and no patients had any signs or symptoms suggestive of NSF. Six patients had the appropriate iron studies, which showed no statistically significant difference in the serum iron, total iron-binding capacity, ferritin, or transferrin saturation before and after exposure to gadopentetate dimeglumine. Our data suggest that the use of gadopentetate dimeglumine in HD patients did not cause iron mobilization and transmetallation therefore may partially explain the lack of development of NSF seen in our patient population.
 ...
PMID:Transmetallation and gadolinium: do low iron stores prevent the development of nephrogenic systemic fibrosis in high-risk end-stage renal disease patients? 2066 51

Receptor-mediated endocytosis, involving megalin and cubilin, mediates renal proximal-tubular reabsorption and is decreased in Dent disease because of mutations of the chloride/proton antiporter, chloride channel-5 (CLC-5), resulting in low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure. To facilitate studies of receptor-mediated endocytosis and the role of CLC-5, we established conditionally immortalized proximal-tubular epithelial cell lines (ciPTECs) from three patients with CLC-5 mutations (30:insH, R637X, and del132-241) and a normal male. Confocal microscopy using the tight junction marker zona occludens-1 (ZO-1) and end-binding protein-1 (EB-1), which is specific for the plus end of microtubules demonstrated that the ciPTECs polarized. Receptor-mediated endocytic uptake of fluorescent albumin and transferrin in 30:insH and R637X ciPTECs was significantly decreased, compared with normal ciPTECs, and could be further reduced by competition with 10-fold excess of unlabeled albumin and transferrin, whereas in the del132-241 ciPTEC, receptor-mediated endocytic uptake was abolished. Investigation of endosomal acidification by live-cell imaging of pHluorin-VAMP2 (vesicle-associated membrane protein-2), a pH-sensitive-GFP construct, revealed that the endosomal pH in normal and 30:insH ciPTECs was similar, whereas in del132-241 and R637X ciPTECs, it was significantly more alkaline, indicating defective acidification in these ciPTECs. The addition of bafilomycin-A1, a V-ATPase inhibitor, raised the pH significantly in all ciPTECs, demonstrating that the differences in acidification were not due to alterations in the V-ATPase, but instead to abnormalities of CLC-5. Thus, our studies, which have established human Dent disease ciPTECs that will facilitate studies of mechanisms in renal reabsorption, demonstrate that Dent disease-causing CLC-5 mutations have differing effects on endosomal acidification and receptor-mediated endocytosis that may not be coupled.
 ...
PMID:Receptor-mediated endocytosis and endosomal acidification is impaired in proximal tubule epithelial cells of Dent disease patients. 2357 77

Congenital disorders of glycosylation are a group of metabolic disorders with an expansive and highly variable clinical presentation caused by abnormal glycosylation of proteins and lipids. Dolichol kinase (DOLK) catalyzes the final step in biosynthesis of dolichol phosphate (Dol-P), which is the oligosaccharide carrier required for protein N-glycosylation. Human DOLK deficiency, also known as DOLK-CDG or CDG-Im, results in a syndrome that has been reported to manifest with dilated cardiomyopathy of variable severity. A male neonate born to non-consanguineous parents of Palestinian origin presented with dysmorphic features, genital abnormalities, talipes equinovarus, and severe, refractory generalized seizures. Additional multi-systemic manifestations developed including dilated cardiomyopathy, hepatomegaly, severe insulin-resistant hyperglycemia, and renal failure, which were ultimately fatal at age 9months. Electrospray ionization mass spectrometric (ESI-MS) analysis of transferrin identified a type I congenital disorder of glycosylation; next-generation sequencing demonstrated homozygous p.Q483K DOLK mutations that were confirmed in patient fibroblasts to result in severely reduced substrate binding and catalytic activity. This patient expands the phenotype of DOLK-CDG to include anatomic malformations and multi-systemic dysfunction.
...
PMID:Severe, fatal multisystem manifestations in a patient with dolichol kinase-congenital disorder of glycosylation. 2414 45

In biological systems, the pH in intracellular organelles or tissues is strictly regulated, and differences of pH are deeply related to key biological events such as protein degradation, intracellular trafficking, renal failure, and cancer. Ratiometric fluorescence imaging is useful for determination of precise pH values, but existing fluorescence probes have substantial limitations, such as inappropriate p Ka for imaging in the physiological pH range, inadequate photobleaching resistance, and insufficiently long excitation and emission wavelengths. Here we report a versatile scaffold for ratiometric fluorescence pH probes, based on asymmetric rhodamine. To demonstrate its usefulness for biological applications, we employed it to develop two probes. (1) SiRpH5 has suitable p Ka and water solubility for imaging in acidic intracellular compartments; by using transferrin tagged with SiRpH5, we achieved time-lapse imaging of pH in endocytic compartments during protein trafficking for the first time. (2) Me-pEPPR is a near-infrared (NIR) probe; by using dextrin tagged with Me-pEPPR, we were able to image extracellular pH of renal tubules and tumors in situ. These chemical tools should be useful for studying the influence of intra- and extracellular pH on biological processes, as well as for in vivo imaging.
 ...
PMID:Development of a Series of Practical Fluorescent Chemical Tools To Measure pH Values in Living Samples. 2968 13

Background:Infectious peritonitis is a clinically important condition contributing to the significant mortality and morbidity rates observed in peritoneal dialysis (PD) patients. Although some of the socioeconomic risk factors for PD-associated peritonitis have been identified, it is still unclear why certain patients are more susceptible than others to infection.Methods:We examined the molecular components of human peritoneal dialysate (HPD) in an attempt to identify factors that might increase patient susceptibility to infection. Characterization studies were performed on initial and follow-up dialysate samples collected from 9 renal failure patients on PD.Results:Our in vitro data showed that peritonitis-causing bacteria grew differently in the patient dialysates. Proteomic analysis identified an association between transferrin presence and infection risk, as peritoneal transferrin was discovered to be iron-saturated, which was in marked contrast to transferrin in blood. Further, use of radioactive iron-labeled transferrin showed peritoneal transferrin could act as a direct iron source for the growth of peritonitis-causing bacteria. We also found catecholamine stress hormones noradrenaline and adrenaline were present in the dialysates and were apparently involved in enhancing the growth of the bacteria via transferrin iron provision. This suggests the iron biology status of the PD patient may be a risk factor for development of infectious peritonitisConclusions:Collectively, our study suggests transferrin and catecholamines within peritoneal dialysate may be indicators of the potential for bacterial growth in HPD and, as infection risk factors, represent possible future targets for therapeutic manipulation.
 ...
PMID:The Iron Biology Status of Peritoneal Dialysis Patients May Be a Risk Factor for Development of Infectious Peritonitis. 3112 76

Anemia of chronic diseases is a condition that accompanies a specific underlying disease, in which there is a decrease in hemoglobin, hematocrit and erythrocyte counts due to a complex process, usually initiated by cellular immunity mechanisms and pro-inflammatory cytokines and hepcidin. This is the second most common type of anemia after iron deficiency anemia in the world. Its severity generally correlates with the severity of the underlying disease. This disease most often coexists with chronic inflammation, autoimmune diseases, cancer, and kidney failure. Before starting treatment, one should undertake in-depth diagnostics, which includes not only assessment of complete blood count and biochemical parameters, but also severity of the underlying disease. The differential diagnosis of anemia of chronic diseases is primarily based on the exclusion of other types of anemia, in particular iron deficiency. The main features of anemia of chronic diseases include mild to moderate lowering of hemoglobin level, decreased percentage of reticulocyte count, low iron and transferrin concentration, but increased ferritin. Due to the increasingly better knowledge of the pathomechanism of chronic diseases and cancer biology, the diagnosis of this anemia is constantly expanding with new biochemical indicators. These include: the concentration of other hematopoietic factors (folic acid, vitamin B12), hepcidin, creatinine and erythropoietin. The basic form of treatment of anemia of chronic diseases remains supplementation with iron, folic acid and vitamin B12 as well as a diet rich in the above-mentioned hematopoietic factors. The route of administration (oral, intramuscular or intravenous) requires careful consideration of the benefits and possible side effects, and assessment of the patient's clinical status. New methods of treating both the underlying disease and anemia are raising hopes. The novel methods are associated not only with supplementing deficiencies, but also with the administration of drugs molecularly targeted to specific proteins or receptors involved in the development of anemia of chronic diseases.
 ...
PMID:Anemia of Chronic Diseases: Wider Diagnostics-Better Treatment? 3256 29

Shiga-toxigenic Escherichia coli (STEC) infection causes severe bloody diarrhea, renal failure, and hemolytic uremic syndrome. Recent studies showed global increases in Locus for Enterocyte Effacement (LEE)-negative STEC infection. Some LEE-negative STEC produce Subtilase cytotoxin (SubAB), which cleaves endoplasmic reticulum (ER) chaperone protein BiP, inducing ER stress and apoptotic cell death. In this study, we report that SubAB induces expression of a novel form of Lipocalin-2 (LCN2), and describe its biological activity and effects on apoptotic cell death. SubAB induced expression of a novel LCN2, which was regulated by PRKR-like endoplasmic reticulum kinase via the C/EBP homologous protein pathway. SubAB-induced novel-sized LCN2 was not secreted into the culture supernatant. Increased intracellular iron level by addition of holo-transferrin or FeCl3 suppressed SubAB-induced PARP cleavage. Normal-sized FLAG-tagged LCN2 suppressed STEC growth, but this effect was not seen in the presence of SubAB- or tunicamycin-induced unglycosylated FLAG-tagged LCN2. Our study demonstrates that SubAB-induced novel-sized LCN2 does not have anti-STEC activity, suggesting that SubAB plays a crucial role in the survival of LEE-negative STEC as well as inducing apoptosis of the host cells.
 ...
PMID:Subtilase cytotoxin induces a novel form of Lipocalin 2, which promotes Shiga-toxigenic Escherichia coli survival. 3314 18


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>