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)

Osteomalacia of cadmium (Cd) poisoning (Itai-Itai disease) is induced by renal tubular dysfunction; however, the precise pathological changes and mechanisms have not been adequately elucidated. Of the 25 inhabitants in a Cd-polluted area who developed chronic tubular proteinuria, 22 individuals died over a 16-year period. Autopsies were performed in 11 cases and osteomalacia was detected in 9 cases (mean age at death 82.2 +/- 7.8 years; 1 man and 8 women). Histologically, osteomalacia occurred coincidentally with diffuse atrophy of the proximal tubules, moderate thickening of the tubular basement membrane and mild interstitial fibrosis in the renal cortex. Ultrastructurally, mitochondria in the proximal tubules were decreased in number and showed abnormal structure, while membrane enzymes, such as 5'-nucleotidase and ALPase, were still well preserved in their brush border. Glomeruli and distal tubules were minimally damaged. Severity of osteomalacia correlated with the damage of the proximal tubules as well as reduced serum calcium (Ca), serum Ca x phosphorus (P) and hematocrit, increased urine beta2-microglobulin, lysozymes, N-acetyl-b-D-glucosaminidase, retinol binding protein, creatinine, and reduced percent tubular reabsorption of phosphate. Multiple regression analysis showed that among these factors, serum Ca x P was an independent factor for predicting the severity of osteomalacia. Our findings suggest that osteomalacia by Cd poisoning causes degenerative changes in the proximal tubules, especially in mitochondria, which might affect the disturbance of the intracellular active transport energy system for calcium and phosphorus, resulting in osteomalacia.
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PMID:Cadmium induces osteomalacia mediated by proximal tubular atrophy and disturbances of phosphate reabsorption. A study of 11 autopsies. 1099 41

Angiotensin II (Ang II) infusion in rats augments vascular injury in balloon-injured carotid arteries and induces marked vascular and tubulointerstitial injury in kidneys. We examined how the AT1 receptor is modulated and whether blockade of the receptor with losartan could prevent the phenotypic and cellular changes. We also examined the role of the local renin-angiotensin system (RAS) by examining the expression of angiotensin-converting enzyme (ACE) and the effect of treatment with the ACE inhibitor, ramipril. Ang II infusion resulted in systemic hypertension and accelerated intimal and medial thickening in balloon-injured carotid arteries. Renal injury was manifested by proteinuria, glomerular phenotypic changes (mesangial expression of alpha-actin and podocyte expression of desmin), and tubulointerstitial injury with the tubular upregulation of the macrophage-adhesive protein, osteopontin, the interstitial accumulation of macrophages and myofibroblasts, and the deposition of collagen types III and IV. Ang II infusion decreased AT1 receptor number in the renal interstitium but not in glomeruli. Losartan completely blocked the Ang II-mediated hypertension, proteinuria, and injury to both carotid and kidney. Ang II infusion was also associated with an increase in ACE protein in both the proximal tubular brush border as well as at interstitial sites of injury, but despite evidence for activation of the local RAS, treatment with ramipril was without effect. These studies demonstrate that the renal and vascular injury induced by Ang II infusion is mediated by the AT1 receptor despite downregulation of the receptor in the interstitium. In addition, although there is evidence for local RAS activation, the injury appears to be mediated solely by the exogenous Ang II.
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PMID:Renal and vascular injury induced by exogenous angiotensin II is AT1 receptor-dependent. 1117 28

Recently, we have developed a tissue-negative staining method, and successfully visualized fine meshwork structure of the glomerular basement membrane (GBM). To clarify the mechanism of proteinuria in active Heymann nephritis, we performed tissue-negative staining and investigated the ultrastructural alterations of the GBM. Active Heymann nephritis, the animal model of human membranous nephropathy, was induced in Lewis rats by the injection of proximal tubular brush border antigen, i.e. Fx1A. Urinary protein excretion was measured and histological studies were performed over 15 weeks following the Fx1A injection. Proteinuria developed at 10 weeks after injection (38.2 +/- 7.4 mg/day) and progressively increased (160.2 +/- 20.6 mg/day at 15 weeks). Capillary fine deposits of IgG and C3 were seen by immunofluorescence, and subepithelial electron dense deposits (EDD) by transmission electron microscopy (TEM). Using the tissue-negative staining method, regular meshwork structure consisted of fine fibrils and pores (2.5 +/- 0.7 nm in short dimension) was observed in the GBM of control rats. At 10 and 15 weeks after injection, the GBM, directly facing the endothelial side of EDD, contained enlarged pores and nephrotic tunnels. Mean values of the short dimension of enlarged pores were 2.9 +/- 0.5 nm at 10 weeks and 3.1 +/- 0.4 nm at 15 weeks, which were significantly larger than that of control rats (p < 0.01). The rest area of the GBM, including newly produced GBM covering the epithelial side of EDD, had no significant difference in size of the pores from control GBM and no tunnels. Although there was no significant difference in the size of enlarged pores between 10 and 15 weeks, the percentage area of GBM with impaired size barrier increased at 15 weeks (51.4 +/- 8.1%) compared with 10 weeks (24.0 +/- 8.3%) and related to severity of proteinuria. The density of the tunnels also increased at 15 weeks. In conclusion, immune deposits may affect the GBM biosynthesis and induce the defect of size barrier of the GBM, which is responsible for proteinuria in active Heymann nephritis.
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PMID:Ultrastructure of glomerular basement membrane in active heymann nephritis rats revealed by tissue-negative staining method. 1142 98

Although it was once considered only a marker of glomerular damage, accumulating evidence indicates that proteinuria per se is nephrotoxic and contributes to the progression of renal injury. Several studies have demonstrated that activation of complement in proteinuric urine results in tubular and interstitial damage. It was previously demonstrated that acute complement-mediated interstitial disease is induced by C5b-9. Here the role of C5b-9 in the progression of chronic proteinuric renal disease was investigated in a nonimmunologic remnant kidney model. Five-sixths nephrectomies were performed for normocomplementemic control and C6-deficient PVG rats. Tubulointerstitial injury was assessed by measurement of two independent markers of tubular injury (i.e., vimentin and osteopontin), interstitial accumulation of the extracellular matrix components collagen type I, collagen type IV, and laminin, interstitial macrophage infiltration, and renal function. The two groups developed similar levels of proteinuria and BP. Whereas C3 deposition on the brush border was equivalent for rats in the two groups, C5b-9 deposition was observed only for normocomplementemic rats. At day 35, the degrees of both tubulointerstitial injury and renal failure were the same for the two groups. Tubulointerstitial injury in normocomplementemic rats was still severe at day 70. In contrast, interstitial injury in C6-deficient rats had improved markedly at day 70, with improvements in renal function. In a rat model of chronic progressive renal disease secondary to nephron loss, the initial interstitial changes are complement-independent and largely reversible, whereas progressive interstitial fibrosis is mediated predominantly by C5b-9. Treatment to reduce C5b-9 attack in tubular cells may slow progression and facilitate recovery.
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PMID:C6 mediates chronic progression of tubulointerstitial damage in rats with remnant kidneys. 1191 52

The complement system is being increasingly implicated in the pathogenesis of progressive renal disease resulting from persistent proteinuria. It has recently been established that renal tubular cells can produce complement, activate complement, and respond to complement activation. Complement proteins that pass through the glomerular barrier along with other serum proteins in the proteinuric state may become activated at the tubular epithelial brush border, and lead to a cascade of events culminating in cell injury. Furthermore, nephrotic components in the urinary space may cause direct activation of the tubular cells to overexpress complement and contribute to local tissue injury. In this review, we will discuss the current evidence supporting a role for complement in the pathogenesis of progressive tubulointerstitial damage in the proteinuric state. The possibility of complement inhibition intervening in progressive tubulointerstitial injury due to proteinuric glomerular disease will also be considered.
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PMID:Role of complement in tubulointerstitial injury from proteinuria. 1207 96

Excessive proteinuria due to loss of glomerular permselectivity in nephrotic syndrome can cause disturbances in renal salt and water handling with edema formation. Apart from oncotic and hydrostatic mechanisms associated with hypoalbuminemia, primary derangements in renal tubular sodium transport may contribute to the pathogenesis of nephrotic edema. Whereas there is evidence for an increase of cortical collecting duct sodium reabsorption in nephrotic rats, it remains controversial whether proximal tubule sodium transport may also be activated in this condition. The regulation of the cortical Na/H exchanger NHE3, the main pathway for Na reabsorption in the proximal tubule (PT), was investigated in rats with puromycin aminonucleoside (PAN)-induced nephrotic syndrome. PAN rats developed reduced GFR, severe proteinuria, and sodium retention within 3 d. After 10 d, immunoblots of brush border vesicles revealed a decreased abundance of NHE3 in nephrotic animals. However, the Na/H antiporter activity in the same vesicle preparations was not significantly altered. Antiporter activity normalized for NHE3 protein was increased by 88% in nephrotic animals (P = 0.025). Immunohistochemistry with the same polyclonal antibody as for immunoblots revealed a decrease of NHE3 abundance in PT. In contrast, immunoreactivity for the monoclonal antibody 2B9, which specifically recognizes the non-megalin-associated, transport-competent pool of NHE3, was higher in PAN-treated rats than in controls. In conclusion, increased sodium reabsorption might be associated with a shift of NHE3 from an inactive pool to an active pool, thus contributing to sodium retention in a state of proteinuria.
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PMID:Regulation of the proximal tubular sodium/proton exchanger NHE3 in rats with puromycin aminonucleoside (PAN)-induced nephrotic syndrome. 1219 63

An autoimmune kidney disease morphologically and functionally similar to Heymann nephritis (HN) was induced in mature male Sprague Dawley rats by repeated weekly IP injections of a chemically modified azo sonicated ultracentrifuged (u/c) rat kidney fraction 3 (rKF3) antigen in an aqueous medium. The experiment was terminated 15 weeks after the first injection of the chemically altered antigen. Serum samples collected and analysed by an indirect fluorescent antibody test on normal rat kidney sections during the course of the experiment showed a gradual rise in circulating pathogenic autoantibodies directed against the proximal tubular brush border regions. Proteinuria was present and significantly increased in the urine of two of eight rats. The arising immune-complex glomerulonephritis (ICGN) revealed typical HN kidney disease lesions in 70% of the rats in histological, direct fluorescent antibody and electron-microscopical examinations. Control rats injected similarly with the an unmodified version of the same antigen did not develop the HN-characteristic morphological and functional changes. To our knowledge, this is the first time that the autoimmune kidney disease designated as an active HN has been produced by the administration of a chemically altered renal antigen in an aqueous solution and not by the usual presentation of the nephritogenic renal antigen in an adjuvant.
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PMID:Production of Heymann nephritis by a chemically modified renal antigen. 1537 60

Dent's disease is an hereditary renal tubular disorder characterized by low-molecular-weight (LMW) proteinuria, hypercalciuria and nephrolithiasis. The disease is due to mutations of CLC-5, a member of the family of voltage-gated CLC chloride channels. CLC-5 is distributed in cells lining the proximal tubule (PT) of the kidney, where it co-localizes with albumin-containing endocytic vesicles that form part of the receptor-mediated endocytic pathway that mediates the reabsorption of low-molecular-weight (LMW) proteins filtered at the glomerular level. Since progression along the endocytic apparatus requires endosomal acidification, it has been suggested that dysfunction of CLC-5 in endosomes may lead to inefficient reabsorption of LMW proteins and dysfunction of PT cells. Investigations conducted in a CLC-5 knockout (KO) mouse model harbouring all the characteristic renal tubular defects of Dent's disease showed a severe impairment of endocytosis by PT cells, such that the endocytic tracer peroxidase was poorly transferred into early endocytic vesicles. These data demonstrated that an impairment of receptor-mediated endocytosis in PT cells is the basis for the defective uptake of LMW proteins in patients with Dent's disease. The endocytosis and processing of LMW proteins involves the multiligand tandem receptors, megalin and cubilin, that are abundantly expressed at the brush border of PT cells. The characterization of the endocytic defect in CLC-5 KO mice revealed that ligands of both megalin and cubilin were affected, whereas a decrease in total kidney content of megalin and cubilin at the protein level was detected. Using analytical subcellular fractionation and quantitative immunogold labelling, we demonstrated a selective disappearance of megalin and cubilin at the brush border of PT cells. These observations allowed us to conclude that defective protein endocytosis linked to CLC-5 inactivation is due to a major and selective loss of megalin and cubilin at the brush border, reflecting a trafficking defect in renal PT cells. These results improve our understanding of Dent's disease, taken as a paradigm for renal Fanconi syndrome and nephrolithiasis, and demonstrate multiple roles for CLC-5 in the kidney. These studies also provided insights in important functions such as apical endocytosis, handling of proteins by renal tubular cells, calcium metabolism, and urinary acidification.
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PMID:Chloride channels and endocytosis: new insights from Dent's disease and CLC-5 knockout mice. 1561 95

Dent's disease is a hereditary renal tubular disorder characterized by low-molecular weight (LMW) proteinuria, hypercalciuria and nephrolithiasis. The disease is due to mutations of ClC-5, a member of the family of voltage-gated CLC chloride channels. ClC-5 is expressed in part in cells lining the proximal tubule (PT) of the kidney, where it colocalizes with albumin-containing endocytic vesicles belonging to the receptor-mediated endocytic pathway that ensures efficient reabsorption of ultrafiltrated LMW proteins. Since progression along the endocytic apparatus requires endosomal acidification, it has been suggested that dysfunction of ClC-5 in endosomes may lead to inefficient reabsorption of LMW proteins and dysfunction of PT cells. Analysis of a ClC-5 knockout (KO) mouse model, displaying all the characteristic renal tubular defects of Dent's disease, showed evidence of a severe LMW proteinuria. Cytochemical studies with the endocytic tracer, peroxidase, showed poor transfer into early endocytic vesicles, suggesting that impairment of receptor-mediated endocytosis in PT cells is the basis for the defective uptake of LMW proteins in patients with Dent's disease. Endocytosis and processing of LMW proteins involve the multiligand tandem receptors, megalin and cubilin, that are abundantly expressed at the brush border of PT cells. Characterization of the endocytic defect in ClC-5 KO mice revealed that ligands of both megalin and cubilin were affected. The total kidney content of megalin and especially cubilin at the protein level was decreased but, more importantly, using analytical subcellular fractionation and quantitative immunogold labelling we demonstrated a selective disappearance of megalin and cubilin at the brush border of PT cells. These observations allowed us to conclude that defective protein endocytosis linked to ClC-5 inactivation is due at least in part to a major and selective loss of megalin and cubilin at the brush border, reflecting a trafficking defect in renal PT cells. These results improve our understanding of Dent's disease, taken as a paradigm for renal Fanconi syndrome and nephrolithiasis, and demonstrate multiple roles for ClC-5 in the kidney. These studies also provided insights into important functions such as apical endocytosis, handling of proteins by renal tubular cells, calcium metabolism, and urinary acidification.
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PMID:Chloride channels and endocytosis: new insights from Dent's disease and ClC-5 knockout mice. 1563 24

Fucoidan, the sulphated polysaccharide extracted from brown seaweed, has various biological activities. The effect of fucoidan on the formation of proteinuria and renal functions in active Heymann nephritis was investigated in this study. Active Heymann nephritis was induced by administering brush border protein of rat proximal uriniferous tubules (FX1A). Fucoidan was administered by oral intubation to Heymann nephritis rats at three doses (50, 100 and 200 mg/kg) once daily for 4 weeks. The elevated urinary protein excretion and plasma creatinine due to the induction of Heymann nephritis were significantly reduced by fucoidan at doses of 100 and 200 mg/kg. The results indicated that fucoidan has a renoprotective effect on active Heymann nephritis and is a promising therapeutic agent for nephritis.
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PMID:Fucoidan inhibits the development of proteinuria in active Heymann nephritis. 1579 3


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