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)

A model has been proposed to explain at least one of the possible pathways through which a xenobiotic might produce proximal tubule necrosis. The model is formulated on the idea that a compound must possess two structural features: (i) a carboxyl or amino acid moiety that would allow for selective uptake into proximal tubule cells via the strategically located antiluminal membrane-bound organic anion transport system or the luminal membrane-bound amino acid transport system(s), respectively, and (ii) a highly reactive moiety that can directly alkylate proximal tubular components, or a moiety that can be biotransformed within proximal tubular cells to such a substance. In an attempt to validate the proposed structural features as prerequisites for xenobiotic induction of proximal tubular necrosis, a novel compound, 4-maleimidohippuric acid (4-MHA), was synthesized which possesses an anionic group and a reactive moiety. Following the administration of 4-MHA directly into the renal artery of pentobarbital-anesthetized dogs, specific unilateral ultrastructural damage was noted only in the S1 and S2 cell types of the proximal tubule; the most notable renal function changes included proteinuria and glucosuria. Anionic, but non-alkylating, relatives of 4-MHA failed to alter renal function or ultrastructure. The specific proximal tubular toxicity of 4-MHA validates the proposed structural requirements for induction of proximal tubular necrosis.
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PMID:4-Maleimidohippuric acid--a tailor-made, direct, site-specific nephrotoxin: effects on renal function and ultrastructure in pentobarbital-anesthetized dogs. 788 82

Proteinuria and tubulointerstitial inflammation (TII) correlate with progression to renal failure in human glomerulonephritis. Various forms of experimental nephrotic syndrome are associated with TII. To study the genesis of TII, we utilized the model of albumin overload. Rats received intraperitoneal bovine serum albumin (BSA) for 1 to 14 days, developing heavy proteinuria. A predominantly macrophage interstitial infiltrate was present at days 3, 7 and 14. The urine of the rats contained a factor chemotactic for macrophages which partitioned into the organic phase with ethyl acetate extraction. TLC and HPLC characteristics were those of a novel, non-polar lipid. Supernatant from the culture of proximal tubule (PT) segments after in vivo or in vitro exposure to high concentrations of lipid-replete BSA showed chemotactic activity with similar chromatographic characteristics. PT cultured with delipidated BSA produced little activity. Thus, the generation of this inflammatory factor occurs as a consequence of tubular metabolism of albumin-borne fatty acids and may contribute to the development of proteinuria-associated TII.
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PMID:Tubular catabolism of albumin is associated with the release of an inflammatory lipid. 793 18

1. Energy dispersive X-ray spectrometry was used to examine the relationship between proteinuria and increased urinary iron excretion, and structural and functional damage in puromycin nephrosis. 2. After 11-12 days rats treated with puromycin (10 mg/100 g, i.v.i.) had greater proteinuria (211.6 +/- 35.7 mg/day, mean +/- s.e.m.) and urinary iron excretion (15.4 +/- 2.2 micrograms/day) than saline-treated controls (14.5 +/- 1.4 mg/day and 1.1 +/- 0.2 micrograms/day, respectively, both P < 0.001). 3. On day 13, mean lysosomal iron concentration of proximal tubular cells (306.6 +/- 64.5 vs 11.9 +/- 8.6 mg%, P < 0.001), and proximal tubular cell damage assessed semi-quantitatively (1.17 +/- 0.10 vs 0.62 +/- 0.10, P < 0.001) were higher and creatinine clearance (0.15 +/- 0.01 vs 0.29 +/- 0.02 mL/min per g kidney weight, P < 0.001) lower than in control rats. 4. At days 35, 60 and 360 there were no differences in any of the measured parameters between rats treated with puromycin or saline, and in both groups proteinuria, tissue damage and lysosomal iron concentration increased with time. 5. Lysosomal iron accumulation was the only independent predictor of both functional and structural damage. 6. In conclusion, the apparent association between proteinuria and tubulo-interstitial damage in puromycin nephrosis, and with ageing, is best explained by factors associated with accumulation of iron within lysosomes of proximal tubule cells.
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PMID:Lysosomal iron accumulation and tubular damage in rat puromycin nephrosis and ageing. 803 74

Proteinuria is a marker of a poor prognosis in the glomerulonephritides and progressive renal disease. Recent animal studies have directly implicated proteinuria in inflammatory tubulointerstitial injury. The proximal tubule takes up significant amounts of lipid in the human nephrotic syndrome. We propose that proximal tubular uptake and metabolism of lipids, notably fatty acid bearing albumin, contributes to the chronic tubulointerstitial infiltration and injury associated with heavy proteinuria. Work in our laboratory has shown that a novel nonpolar lipid released by proximal tubules endocytosing fatty acid-bearing albumin is a potent macrophage chemoattractant. We have also studied the metabolic destiny of fatty acids liberated upon proximal tubular catabolism of albumin. Palmitate was preferentially metabolized to phosphatidylcholines, phosphatidylinositols and diglycerides. Oleate and linoleate were metabolized to triglycerides. Palmitate was profoundly inhibitory to OK cell growth, whilst oleate was stimulatory. In nephrosis, faced with an unregulated influx of fatty acids on albumin, the proximal tubule metabolizes them to a variety of lipids, some of which have pathological effects. Thus, the metabolism of albumin-bound fatty acids by the proximal tubule during heavy proteinuria may directly underlie subsequent tubulointerstitial inflammation and altered response to injury.
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PMID:Contribution of proteinuria to progressive renal injury: consequences of tubular uptake of fatty acid bearing albumin. 811 91

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is an established nephrotoxicant in male Fischer 344 rats at i.p. doses of > or = mmol/kg. Since gender differences often exist in the susceptibility to toxicants, the nephrotoxic potential of NDPS was examined in female Fischer 344 rats. Rats (4-5/group) were administered NDPS (0.1, 0.2, 0.4, or 1.0 mmol/kg, i.p.) or vehicle (sesame oil, 2.5 ml/kg) and renal function monitored for 48 h. At a dose of 0.1 mmol/kg, NDPS had no effect on renal function. However, administration of NDPS at a dose of 0.2 or 0.4 mmol/kg resulted in marked nephrotoxicity characterized by diuresis, increased proteinuria, glucosuria, hematuria, elevated blood urea nitrogen (BUN) concentration and kidney weight, decreased organic ion accumulation and proximal tubular necrosis. NDPS treatment of 1.0 mmol/kg resulted in oliguric renal failure rather than polyuric renal failure in 3 of 4 rats. Proximal tubular damage was observed primarily in the S3 segment of the proximal tubule in NDPS-treated female rats, while in male rats the S1 and S2 segments are the initial renal targets. These results demonstrate that female Fischer 344 rats are more susceptible to NDPS nephrotoxicity than male Fischer 344 rats and that the site of the renal lesion is gender dependent.
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PMID:Acute N-(3,5-dichlorophenyl)succinimide nephrotoxicity in female Fischer 344 rats. 816 Jan 97

We investigated the possible renal protective effects of KW-3902 (8-(noradamantan-3-yl)-1,3-dipropylxanthine), a selective and potent adenosine A1-receptor antagonist, against cephaloridine (CER)-induced acute renal failure (ARF) in rats. ARF was induced by intravenous injection of CER at a dose of 600 mg/kg body weight. KW-3902 at doses higher than 0.01 mg/kg (p.o.) dose-dependently attenuated the decrease of creatinine clearance and the increase of proteinuria in rats with CER-induced ARF. In contrast, furosemide and trichlormethiazide (TCM) increased urinary protein and aggravated the serum parameters. These results suggest that KW-3902 has some advantages over furosemide and TCM when used in combination with CER. In the diuretic study in the rats with established ARF induced by CER, KW-3902, furosemide and TCM caused a significant increase in sodium excretion, whereas acetazolamide was ineffective. These results suggest that the proximal tubule is functionally damaged in rats with CER-induced ARF, in accord with the histological observation demonstrating the degeneration of the proximal tubule. From the fact that KW-3902 induces diuretic action even in CER-induced ARF, it is suggested that KW-3902 acts, directly or indirectly, on the proximal tubule or other tubular sites in the kidney, resulting in the diuretic effect.
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PMID:Effects of KW-3902, a novel adenosine A1-receptor antagonist, on cephaloridine-induced acute renal failure in rats. 816 96

Cyclosporin (CsA) induces autophagolysosomes in proximal tubules. A major lysosomal function is degradation of cell proteins. Cathepsin B and L are marker enzymes for the activity of lysosomal protein degradation. Therefore we measured cathepsin activities in microdissected proximal tubule segments and urine from rats treated with CsA, 30 mg/24 h by gavage for 42 days. Cathepsin activity was increased in proximal tubule by 117% and in 24-h urine by 37% compared to controls. Unchanged values of serum cathepsin activity and of proteinuria excluded increased glomerular filtration or decreased tubular absorption as major source of urine cathepsins. Therefore urine cathepsin excretion reflected tubular cathepsin activity. Urine cathepsin excretion was also measured in patients without renal disease treated with CsA for multiple sclerosis (MS). It was increased by 59% in patients with CsA serum values > 120 ng/ml compared to MS patients without CsA or with serum CsA < 120 ng/ml. Urine cathepsin excretion increased linearly with serum CsA (P < 0.001). The data suggest that cathepsin activity is increased in proximal tubules of CsA-treated patients. Hence CsA may stimulate protein degradation in proximal tubules of men and rats.
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PMID:Effect of cyclosporin on kidney proteolytic enzymes in men and rats. 817 72

Metabolic acidosis is a well-known mediator of compensatory renal hypertrophy; however, the underlying mechanism is still poorly understood. The aim of the present study was to investigate whether metabolic acidosis can influence the proteolytic activity in the proximal tubule. Metabolic acidosis was induced in rats by 0.28 M NH4Cl which was mixed to drinking water. The development of metabolic acidosis was documented by a significant increase in urinary pH. After 11 days of 0.28 M NH4Cl treatment, the experimental animals developed mild proteinuria (9.52 +/- 0.99 versus 17.65 +/- 1.63 mg/day). The kidney weight increased significantly (1,653.56 +/- 27.84 versus 1,753.33 +/- 56.11 mg) and tubular proteinase activity, measured at pH 5.4, was markedly reduced (60.3 +/- 1.2 versus 52.2 +/- 2.4 U/mg protein, or 2,105.5 +/- 92.0 versus 1,631.0 +/- 97.2 mU/micrograms DNA). In summary, these results suggest that compensatory renal hypertrophy induced by metabolic acidosis might at least partly be due to the suppression of tubular proteinase activity.
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PMID:Effect of metabolic acidosis on tubular proteinase activity. 819 Jan 89

We have previously reported that isoproterenol induces type 2 salivary cystatin in both submandibular glands and kidney tubule cells of rats but not in any other organs examined. In the present study, we investigated whether this salivary protein is induced in other conditions that show kidney tubule injury. Immunocytochemistry, using a monospecific antiserum to this cystatin, revealed specific staining within the proximal tubule epithelium of the cortex as well as in the inner and outer stripe of the medulla of immunologically and chemically injured rats. Cystatin could not be detected in kidneys from healthy rats by means of immunocytochemistry. Weak staining was found in 3/3 kidneys of rats treated with turpentine and in 5/5 animals treated with potassium dichromate. In rats treated with puromycin, cystatin could not be demonstrated in 5/5 animals having proteinuria of less than 100 mg/24 h; however, moderate staining was observed in 4/5 puromycin-treated rats having proteinuria greater than 100 mg/24 h. In Heymann nephritis, cystatin was present in 7/31 kidneys with proteinuria lasting 6 to 15 weeks and in none (0/7) with proteinuria of shorter duration. Strong staining was also observed in 10/10 kidneys from rats with moderate-to-severe chronic serum sickness. This study shows that elaboration of type 2 cystatin in rats is not limited to salivary glands and, with our previous study, suggests that induction of this cysteine inhibitor may represent a local response to generalized tissue injury in both submandibular and renal tissues. These findings further demonstrate that induction of cystatin in salivary glands is not unique to these glands and suggest that induction of this cysteine proteinase inhibitor may represent a local response to tissue injury caused by diverse mechanisms.
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PMID:Induction of type 2 salivary cystatin in immunological and chemical kidney injury. 837 10

Renal proximal tubule cell injury is an important side effect of the chemotherapeutic agent ifosfamide in humans. We investigated the effect of this medication on kidney function in rats. Animals received either 40 or 80 mg kg(-1) ifosfamide intraperitoneally daily for 3 days every 3 weeks for a total of four treatment courses. Ifosfamide-treated rats had significantly lower body weight and hematocrit than sterile water-treated control rats. Animals receiving 40 mg kg(-1) ifosfamide developed isolated phosphaturia after their fourth and final treatment course. Rats receiving 80 mg kg(-1) ifosfamide had low-grade glucosuria, phosphaturia and proteinuria throughout the study. Urine flow rate, creatinine clearance, urinary sodium and potassium excretion and kidney glutathione and malondialdehyde content were not affected by ifosfamide at either dose. These findings indicate that ifosfamide produces abnormalities in rat renal function resembling subclinical Fanconi syndrome.
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PMID:Nephrotoxicity of ifosfamide in rats. 866 24


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