Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although hyperlipidemia is a well recognized complication of the nephrotic syndrome, the precise disturbances of lipoprotein metabolism which cause the elevated plasma lipid and lipoprotein concentrations have not been clearly defined in humans. This study examines the metabolism of apolipoprotein B-containing lipoproteins in patients with nephrotic-range proteinuria and in healthy controls. Two radioiodinated tracers of very low density lipoproteins (VLDL1, Sf60 to 400, and VLDL2, Sf20 to 60), were used to trace the metabolism of apolipoprotein B through the delipidation cascade from very low density lipoproteins (VLDL) to low density lipoproteins (LDL). The data from the apoB specific radioactivity curves and the pool sizes of apoB in four subfractions were analyzed by a multicompartmental modeling procedure using the SAAM 30 program. The main findings in the nephrotic group were: 1.) a consistent decrease in the fractional rate of apoB transfer from VLDL1----VLDL2 (median values-nephrotic 0.92 pools/day vs. controls 3.66, P less than 0.02) and from VLDL2----IDL (1.49 vs. 2.74, P less than 0.05); 2.) increased secretion of apoB into VLDL2 (14.5 mg/kg/day vs. 4.2, P less than 0.02); 3.) a trend towards decreased removal of IDL and LDL attributable to a defect in LDL receptor-mediated removal as previously shown (Metabolism 39:187-192, 1990). These findings suggest that catabolic defects of the apo B-containing lipoproteins are as important as increased hepatic synthesis in the pathogenesis of nephrotic hyperlipidemia in humans.
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PMID:Metabolism of apolipoprotein B-containing lipoproteins in subjects with nephrotic-range proteinuria. 192 Nov 48

Hyperlipoproteinemia is frequently observed in patients after renal transplantation and contributes to cardiovascular morbidity and mortality. In addition, it was recently shown that hypercholesterolemia accelerates the progression of renal disease. In a renal transplant recipient (RTR) with severe coronary heart disease, familial hypercholesterolemia and decreased renal function, immunospecific LDL-apheresis was instituted since dietary restrictions failed to sufficiently improve hyperlipoproteinemia and medication had to be avoided due to drug interactions. Over a period of 36 months 145 LDL-apheresis treatments were performed at weekly intervals. The desorption of 5600 ml plasma volume allowed a mean reduction of total cholesterol by 56.6% (from 256 mg/dl to 110 mg/dl), of LDL-cholesterol by 63.0% (from 163 mg/dl to 58 mg/dl), of Lp(a) by 68.3% (from 34 mg/dl to 11 mg/dl) and of triglycerides by 49.6% (from 332 mg/dl to 163 mg/dl). Although temporarily decreasing during each apheresis session by 9.0%, HDL-cholesterol values increased during the first 9 months of treatment and remained within the normal range (> 45 mg/dl) thereafter. Cyclosporine A blood trough values were decreased by 32% during LDL-apheresis. Symptoms of angina pectoris rapidly improved and disappeared after 8 months of apheresis treatment. Initial coronary angiography exhibited serious three-vessel-disease, without the possibility of bypass grafting. Coronary angiography repeated after two years of therapy showed a regression of the disease. Serum creatinine levels declined during treatment (from 2.7 mg/dl to 1.8 mg/dl) and proteinuria did not increase further. This is the first report to show that long-term LDL-immunoadsorption is a safe and highly effective treatment of severe hyperlipidemia and coronary heart disease in a RTR, resulting in regression of vascular pathology. Moreover, amelioration of hyperlipidemia may have improved transplant function. Multicenter studies are necessary to confirm our results.
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PMID:Regression of coronary atherosclerosis and amelioration of renal function during LDL-immunoadsorption therapy in a renal transplant recipient. 878 84

Hyperlipidemia is an established risk factor for progressive renal damage and proteinuria. Platelets and vascular smooth muscle cells (VSMC) are known to possess low density lipoprotein (LDL) cholesterol receptors. We used platelet LDL receptors to investigate the hypothesis that elevated lipids could activate intracellular calcium [Ca2+]i signals, leading to altered vascular tone and permeability. We divided essential hypertensives into microalbuminuric positive (MA+) and negative (MA-) groups and measured baseline and LDL stimulated levels of [Ca2+]i. The MA+ group demonstrated a significantly higher mean baseline [Ca2+]i level (119.0 +/-24.5 v 86.2 +/- 25.4 micromol/mL, P = .001). The MA+ group also displayed greater elevations in [Ca2+]i levels after stimulation with LDL in concentrations of 10 and 25 microg/mL (100.9 +/- 54.8 v 40.9 +/- 20.2, P = .04 and 111.6 +/- 51.0 v 52.9 +/- 39.9 micromol/mL, P = .03, respectively). Our data indicate that hypertensive patients with early glomerular capillary injury display exaggerated influx of [Ca2+]i after LDL receptor stimulation. Heightened LDL receptor sensitivity may facilitate LDL mediated [Ca2+]i signals, leading to increased VSMC tone and proliferation and progressive renal disease.
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PMID:Low density lipoprotein receptors mediate intracellular calcium signals in microalbuminuric hypertensives. 950 58

Lectinlike oxidized LDL receptor-1 (LOX-1), a cell-surface receptor for oxidized LDL (ox-LDL), is proposed to be involved in endothelial dysfunction and in the pathogenesis of atherosclerosis. Preeclampsia is a pregnancy complication diagnosed by hypertension and proteinuria, characterized by endothelial dysfunction, and supposedly caused by compounds from hypoxic uteroplacental tissues. A feature of preeclampsia is formation of foam cells in maternal arterial walls of gestational tissue ("acute atherosis"). Oxidative stress is believed to play a role in the pathophysiology of preeclampsia. 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) is a marker of oxidative stress in vivo, is biologically active in vitro, and is elevated in preeclamptic plasma and gestational tissue. In the present article, we hypothesized that 8-iso-PGF(2alpha) could induce the expression of LOX-1 in trophoblastic cells (JAR). We demonstrated augmented cellular uptake of (125)I-tyraminylcellobiose ox-LDL in JAR cells incubated with 8-iso-PGF(2alpha) (10 micromol/L) versus control cells. Ligand blots revealed an increased binding of ox-LDL to LOX-1 in JAR cells incubated with 8-iso-PGF(2alpha) (10 micromol/L). Incubation with 8-iso-PGF(2alpha) (10 micromol/L) also resulted in augmented LOX-1 protein levels (Western blots) and mRNA levels (Northern blots). JAR cells transfected with 3 copies of a nuclear factor-kappaB binding site demonstrated dose-dependent activation of the reporter gene luciferase after incubation with 8-iso-PGF(2alpha) (0 to 10 micromol/L). We also demonstrated increased accumulation of neutral fats in JAR cells incubated with 8-iso-PGF(2alpha) (10 micromol/L) and ox-LDL compared with controls by oil red O staining. We speculate a potential role of isoprostanes and LOX-1 in preeclampsia in the development of "acute atherosis" of gestational spiral arteries.
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PMID:8-iso-prostaglandin F(2alpha) increases expression of LOX-1 in JAR cells. 1130 22

A microemulsion formulation of cyclosporin (Neoral) has been developed to overcome the problems of poor and variable absorption of cyclosporin. Neoral is a potent immunosuppressive agent that is highly bound in the plasma. It has been proposed that low-density lipoprotein (LDL) delivers cyclosporin (CsA) to T-lymphocytes via the LDL receptor pathway, where it produces its therapeutic effects. Herein, we report a case of minimal change nephrotic syndrome with type 2 diabetes mellitus treated by Neoral and fluvastatin. A 65-year-old male with a 10-year history of type 2 diabetes mellitus suddenly developed nephrotic syndrome. The potential causative drugs, such as NSAIDs and antibiotics, had not been administered. The laboratory findings were as follows: proteinuria 23 g/day, serum albumin 1.9 g/dl, total cholesterol 629 mg/dl, LDL-Cho 1,930 mg/dl. Renal biopsy was normal on light microscopy, and immunofluorescence demonstrated no staining. Due to the risk of deterioration of diabetes by administering prednisolone, he was given Neoral at 2.0 mg/kg/day. He was also given fluvastatin (40 mg/day) for hyperlipidemia after the renal biopsy. At four weeks after the start of Neoral and fluvastatin, his nephrosis continued, but his LDL-Cho and total cholesterol decreased. At six weeks after treatment, proteinuria gradually reduced. At eight weeks after treatment, the proteinuria had disappeared. Nephrotic syndrome is often associated with abnormal lipid metabolism, and many patients with nephrotic syndrome show high levels of LDL-Cho. It has been reported recently that LDL apheresis is effective against nephrotic syndrome. However, in the present case, it can be speculated that the improvement of hyperlipidemia by fluvastatin probably augmented the effect of Neoral, presumably through the increased cellular uptake of Neoral. This suggests that fluvastatin may be considered as the treatment of choice for the disturbed lipoprotein profile in patients with nephrotic syndrome.
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PMID:[Complete remission of minimal change nephrotic syndrome with type 2 diabetes mellitus treated by microemulsion formulation of cyclosporin and fluvastatin]. 1197 50

Nephrotic syndrome (NS) is characterized by the presence of proteinuria and hyperlipidemia. However, ingestion of soy protein has a hypolipidemic effect. The present study was designed to determine whether the ingestion of a 20% soy protein diet regulates the expression of hepatic sterol regulatory element binding protein (SREBP)-1, fatty acid synthase (FAS), malic enzyme, beta-hydroxy-beta-methylglutaryl-CoA (HMG-CoA) reductase (r) and synthase (s), and LDL receptor (r), and to assess whether soy protein improves lipid and renal abnormalities in rats with chronic NS. Male Wistar rats were injected with vehicle or with puromycin aminonucleoside to induce NS and were fed either 20% casein or soy protein diets for 64 d. NS rats fed 20% soy protein had improved creatinine clearance and reduced proteinuria, hypercholesterolemia, hypertriglyceridemia, as well as VLDL-triglycerides and LDL cholesterol compared with NS rats fed the 20% casein diet. In addition, the soy protein diet decreased the incidence of glomerular sclerosis, and proinflammatory cytokines in kidney. Ingestion of the soy protein diet by control rats reduced the gene expression of SREBP-1, malic enzyme, FAS and increased HMG-CoAr, HMG-CoAs and LDLr. However, NS rats fed either casein or soy protein diets had low insulin concentrations with reductions in SREBP-1, FAS and malic enzyme expression compared with control rats fed the casein diet. NS rats fed the soy diet also had lower HMG-CoAr and LDLr mRNA levels than NS rats fed casein. In conclusion, the beneficial effects of soy protein on lipid metabolism are modulated in part by SREBP-1. However, in NS rats, the benefit may be through a direct effect of this protein on kidney rather than mediated by changes in expression of hepatic lipid metabolism genes.
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PMID:A soy protein diet alters hepatic lipid metabolism gene expression and reduces serum lipids and renal fibrogenic cytokines in rats with chronic nephrotic syndrome. 1222 Dec 9

Hypercholesterolemia is a main feature of nephrotic syndrome (NS) and is, in part, caused by acquired low-density lipoprotein (LDL) receptor deficiency. The LDL receptor deficiency in NS is accompanied by normal hepatic LDL receptor messenger RNA (mRNA) abundance. Expression of LDL receptor, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and several other cholesterol-regulatory factors is regulated by sterol regulatory element binding protein 2 (SREBP-2). This study tested the hypothesis that nephrotic hypercholesterolemia may be associated with dysregulation of hepatic tissue SREBP-2 abundance or activity. Protein and mRNA abundance of SREBP-2, LDL receptor, and HMG-CoA reductase was determined in the livers of rats with chronic puromycin-induced NS and of control rats. The nephrotic group showed heavy proteinuria, hypoalbuminemia, severe hypercholesterolemia, and normal liver tissue total and free cholesterol concentrations. Despite severe hypercholesterolemia, the inactive microsomal and the active nuclear SREBP-2 levels were unchanged in the liver of the nephrotic animals. This was associated with a marked reduction in LDL receptor protein abundance. In confirmation of our earlier studies, LDL receptor and HMG-CoA reductase mRNA levels were unchanged in nephrotic animals. Hepatic SREBP-2 abundance and activity in hypercholesterolemic nephrotic rats were similar to those found in the normocholesterolemic control animals, representing a maladaptive response. This paradox may be, in part, due to acquired LDL receptor deficiency that helps sustain SREBP-2 expression/activity and maintain hypercholesterolemia by limiting hepatic cholesterol uptake. This is because SREBP-2 expression and activity are, in part, regulated by intracellular as opposed to plasma cholesterol.
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PMID:Hepatic tissue sterol regulatory element binding protein 2 and low-density lipoprotein receptor in nephrotic syndrome. 1788 48

Mice lacking the LDL receptor associated protein (RAP) have a severe defect of thyroglobulin secretion into the colloid, associated with moderately increased serum TSH levels and histological features of early goiter. RAP is expressed also in renal proximal tubule cells, where it functions as a molecular chaperone for the endocytic receptor megalin, which is responsible for reabsorption of low molecular weight proteins from the glomerular filtrate. Here we investigated whether the thyroid phenotype in RAP knockout (KO) mice is associated with kidney alterations. By immunohistochemistry, we found that in RAP KO mice megalin expression on the apical membrane of renal proximal tubule cells was markedly reduced, with intracellular retention of the receptor. The reduced expression of megalin was associated with its impaired function. Thus, urinary protein concentrations and urinary protein excretion in 24 h were higher in RAP KO than in wild-type mice. Coomassie staining of urine samples revealed an increased intensity of low molecular mass bands in the urine of RAP KO mice, indicating that they had low molecular weight proteinuria. Therefore, we concluded that disruption of the RAP gene determines not only thyroid abnormalities, but also a severe defect of megalin expression and function in the kidney.
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PMID:Kidney abnormalities in low density lipoprotein receptor associated protein knockout mice. 1829 6

Megalin, a member of the LDL receptor family, is expressed on the apical membrane of proximal tubules and serves as an endocytic scavenger of filtered proteins and hence might contribute to the tubule injury as a consequence of glomerular disease. To study its role, we crossed megalin knockout mosaic mice (lacking megalin expression in 60% of proximal tubule cells) with NEP25 mice (a transgenic line expressing human CD25 in the podocyte). Treatment of this transgenic mouse with the immunotoxin causes nephrotic syndrome, focal segmental glomerulosclerosis and tubule-interstitial injury. Following this treatment, the double transgenic mice had massive non-selective proteinuria and mild glomerular and tubular injury. Comparison of megalin-containing to megalin-deficient proximal tubule cells within each kidney showed that albumin, immunoglobulin light chain, IgA and IgG were preferentially accumulated in proximal tubule cells expressing megalin. Tubule injury markers such as heme-oxygenase-1, monocyte chemoattractant protein-1 and cellular apoptosis were also preferentially found in these megalin-expressing cells. These results show that megalin plays a pivotal role in the reabsorption of small to large molecular size proteins and provides direct in vivo evidence that reabsorption of filtered proteins triggers events leading to tubule injury.
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PMID:Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria. 1897 59

Agents that inhibit glycation end products by reducing the carbonyl load from glycation and glycoxidation are an emerging pharmacologic approach to treat complications of diabetes. We previously demonstrated that antibodies generated to the glycoprotein keyhole limpet hemocyanin (KLH) can cross-link with reactive carbonyl residues on protein conjugates. Here, we immunized streptozotocin-induced diabetic rats with KLH to assess the capacity of the elicited antibodies to intercept carbonyl residues on glycated proteins and to mitigate glycation-related pathology. Compared with diabetic rats immunized with adjuvant alone, KLH-immunized diabetic rats had decreased levels of glycated peptides in sera and demonstrated a reduction in albuminuria, proteinuria, deposition of glycation end products in the kidney, and histologic damage. In vitro, low molecular weight glycated peptides from rat serum reacted with anti-KLH antibodies at a faster rate than normal IgG and selectively modified the lambda chains. The reaction products contained peptide sequences from type I collagen alpha chain, albumin, and LDL receptor-related protein. These adduction reactions were inhibited by free KLH and by reduction of glycated peptides with borohydride. In summary, these results suggest that inherent reactivity of Ig light chains provides a natural mechanism for the removal of cytotoxic glycation products. This reactivity can be augmented by glycoprotein-specific reactive immunization, a potential biopharmaceutical approach to glycation-related pathology.
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PMID:Reactive immunization suppresses advanced glycation and mitigates diabetic nephropathy. 1938 54


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