maleic-acid and Proteinuria

Heme oxygenase-1 (HO-1), a cytoprotective gene, is commonly induced in renal tubules in the diseased kidney. Because proteinuria is a hallmark for kidney disease, we examined the relationship between proteinuria and tubular induction of HO-1, specifically questioning whether increased trafficking of protein across the renal tubular epithelium, as a consequence of proteinuria, induces tubular expression of HO-1. We examined a model of glomerular proteinuria induced by daily injections of BSA, which is associated with increased tubular uptake of filtered protein, and a model of tubular proteinuria induced by maleate, the latter exhibiting decreased tubular uptake and trafficking of protein. The BSA model of glomerular proteinuria failed to exhibit induction of HO-1; HO-1 was not induced in proximal tubular epithelial cells exposed to BSA. In contrast, in maleate nephropathy wherein tubular uptake of protein is decreased because of generalized proximal tubular injury induced by maleate, HO-1 was strongly induced in proximal tubules; inhibition of HO activity in maleate nephropathy worsened proteinuria, renal histological injury, and apoptosis. In renal proximal tubular epithelial cells, maleate induced HO-1 and caused apoptosis, the latter increased when HO activity was inhibited. From these studies, we conclude that expression of HO-1 in the diseased kidney cannot be ascribed to the tubular uptake and metabolism of protein such as albumin, and that the expression of HO-1 in a model of tubular proteinuria reflects a functionally significant stress response to toxin-induced proximal tubular injury.

Topics: Animals; Apoptosis; Disease Models, Animal; Glomerular Mesangium; Heme Oxygenase-1; Kidney; Kidney Tubules, Proximal; Maleates; Proteinuria; Rats; Rats, Wistar; Serum Albumin, Bovine

A controversy presently exists concerning the ability of albumin to inhibit the tubular reabsorption of low-molecular-weight (M(r)) proteins in experimental renal diseases leading to massive proteinuria. We have examined the urinary excretion of albumin and of 2 low-M(r) proteins, beta 2-microglobulin and cystatin C, in rats treated with toxins affecting primarily the glomerulus (puromycin amino-nucleoside and Adriamycin) or the tubule (mercuric chloride and maleic acid). Above a threshold of 100 mg/24 h, albuminuria induced by puromycin aminonucleoside (50 mg/kg) and Adriamycin (5 mg/kg) was associated with a marked increase in the urinary excretion of beta 2-microglobulin and cystatin C peaking at more than 100-fold the baseline levels. These glomerulotoxins did not affect the urinary excretion of the tubular enzyme N-acetyl-beta-D-glucosaminidase. This pattern of effects was completely different from that induced by mercuric chloride (2 mg/kg) and maleic acid (400 mg/kg) which increased the excretion of both N-acetyl-beta-D-glucosaminidase and low-M(r) proteins in rats with albuminuria values below 100 mg/24 h. These results strongly support the hypothesis that at high filtered loads, albumin decreases the tubular uptake of low-M(r) proteins most likely by competition for a common transport mechanism.

Topics: Acetylglucosaminidase; Albumins; Animals; beta 2-Microglobulin; Binding, Competitive; Biological Transport, Active; Cystatin C; Cystatins; Doxorubicin; Kidney Diseases; Kidney Tubules; Male; Maleates; Mercuric Chloride; Molecular Weight; Proteins; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley

The relationship between tubulointerstitial nephritis and proteinuria was characterized in experimental nephrosis in rats. In one group, proteinuria induced by aminonucleoside of puromycin (PAN) was reduced by using an 8% protein diet and adding the angiotensin I-converting enzyme (ACE) inhibitor enalapril to the drinking water. Two control groups were injected with saline and PAN, respectively, and fed a 27% protein diet. The first group had significantly reduced albuminuria and a definite attenuation of tubular cell injury. There was a strong positive correlation between the number of interstitial macrophages and albuminuria. The beneficial effect was reproduced by dietary-protein restriction alone, whereas ACE inhibition alone had an insignificant effect on the degree of proteinuria. Depletion of circulating T lymphocytes in one group of nephrotic rats eliminated interstitial lymphocytes but did not affect interstitial macrophage influx. Inhibition of the in situ proliferation of resident interstitial macrophages by unilateral kidney irradiation failed to change the intensity of the macrophage infiltration. Treatment of rats with sodium maleate produced proximal tubular cell toxicity but interstitial inflammation did not develop, suggesting that the latter is not a nonspecific response to tubular injury. These studies demonstrate a strong relationship between tubulointerstitial nephritis and the severity of proteinuria in experimental nephrosis.

Topics: Acute Disease; Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Division; Dietary Proteins; Disease Models, Animal; Enalapril; Female; Kidney; Lymphocyte Depletion; Macrophages; Maleates; Nephritis, Interstitial; Nephrotic Syndrome; Proteinuria; Puromycin; Rats; Rats, Inbred Lew

The effects of maleate on membrane-bound and lysosomal peptidases were studied histochemically in the kidney and biochemically in the kidney and the urine of male and female rats 6 h after the administration of two different doses of sodium maleate (150 and 300 mg/kg body weight). Additionally, the proteinuria of experimental animals was electrophoretically analysed to detect maleate-induced alterations in the urinary protein composition. The histochemistry of the brush-border peptidases (aminopeptidase A, gamma-glutamyltransferase) showed dose-dependent maleate effects in the late pars convoluta and the pars recta of the proximal tubule (blurring of the brush-border enzyme reaction pattern). The female animals were more severely affected by both maleate doses. After maleate treatment, enzyme-activity measurements in the kidney homogenate supernatant and urine indicated dose-dependent structural destruction of the proximal tubule, especially of brush-border membranes, and revealed an increase in enzyme excretion. Both the maleate-induced enzyme excretion and proteinuria were more pronouncedly increased in females than in males. Electrophoretic analysis of urinary proteins revealed alterations in the urinary-protein composition after maleate treatment, which favoured the excretion of proteins with a molecular weight higher than 20,000 daltons. Again, sex-related differences in the maleate effects were demonstrated. The results indicate that maleate causes alterations in the brush-border membranes and, especially at higher doses, results in cellular destruction selectively in the late proximal tubule of rat kidneys. Selectivity was also encountered in the maleate effects on urinary-protein composition, suggesting that the tubular alterations lead to an inhibition of the reabsorption of mainly high-molecular-weight proteins. Although the nature of the effects was independent of sex, it appears that females are less well protected against tubular damage caused by maleate.

Topics: Aminopeptidases; Animals; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Endopeptidases; Female; gamma-Glutamyltransferase; Glutamyl Aminopeptidase; Histocytochemistry; Injections, Intraperitoneal; Kidney; Kidney Glomerulus; Kidney Tubules; Male; Maleates; Proteinuria; Rats; Rats, Inbred Strains; Sex Factors

In several models of acute renal failure leakage of glomerular filtrate out of the tubule is an important pathogenetic mechanism; however, bidirectional diffusion of solute to account for certain pathophysiologic features of acute renal failure has received meager attention. Using micropuncture and clearance methods, we assessed sequentially leakage of solutes and inulin across proximal straight tubules (PST) injured by two nephrotoxins. In d-serine-treated rats with extensive necrosis of PST, the basis for glucosuria and tubular leakage of inulin was studied. Glucose absorption by the proximal convoluted tubule and glucose delivery to the PST were normal, but glucose delivery to the distal tubule was increased nearly 8-fold, indicating diffusion of glucose from interstitial to tubular luminal fluid across the necrotic PST. Total kidney inulin clearance was greatly reduced, but single nephron glomerular filtration rate, based on proximal convoluted tubule samples, was normal, indicating tubular loss of inulin. Urinary recovery of [14C]inulin infused into tubular lumina revealed that proximal convoluted tubule and distal tubule were impermeable to inulin and that inulin diffused out of the necrotic PST. The progressive return over 6 days of tubular impermeability for inulin correlated with relining of PST with new cells. In maleic acid-treated rats the site and extent of tubular necrosis and the nature of urinary loss of solutes were studied. Microdissection revealed that maleic acid caused limited necrosis of PST which averaged 7.4% of total proximal tubular length. Increased urinary excretion of protein, phosphate, and glucose and increased tubular permeability to microinfused [14C]inulin occurred with the onset of PST necrosis, and return of these abnormalities to normal correlated with the degree of cellular repair of the PST. Together these data indicate that with severe cellular injury there is bidirectional, concentration-dependent diffusion of solutes between the interstitial and tubular fluids. Thus, experimental or human toxic nephropathies should not be classified as acquired Fanconi's syndrome unless specific tubular transport defects are present.

Topics: Acute Kidney Injury; Animals; Carbon Radioisotopes; Glomerular Filtration Rate; Glucose; Glycosuria; Inulin; Kidney Tubules; Male; Maleates; Phosphates; Proteins; Proteinuria; Rats; Rats, Inbred Strains; Serine

The normal filtered load of albumin at the rat glomerulus was estimated to be 18 mg/24 h X g kidney weight by means of micropuncture studies. Total nephron fractional reabsorption was 91%. The proximal convoluted tubule accounted for 72% of total reabsorption followed by an additional 12% in the loop of Henle. Only minimal protein uptake occurred in more distal parts of the nephron. Na maleate, given at a dosage of 2 mM/kg body weight 2 h prior to micropuncture, inhibited tubular albumin uptake in the proximal convoluted tubule. As in controls there was no measurable protein uptake beyond the loop of Henle. These results indicated that tubular reabsorption of albumin was virtually completed by the early distal convoluted tubule. Maleate was found to be a potent inhibitor of protein transport in the proximal convoluted tubule resulting in a fractional excretion of albumin of 50%.

Topics: Animals; Kidney Tubules; Kidney Tubules, Distal; Kidney Tubules, Proximal; Male; Maleates; Proteinuria; Rats; Rats, Inbred Strains; Serum Albumin

Topics: Animals; Creatinine; Glycosuria; Kanamycin; Kidney Diseases; Male; Maleates; Metals; Molecular Weight; Proteinuria; Rabbits; Renal Aminoacidurias

Nephrotoxic agents such as puromycin aminonucleoside (PAN) and sodium maleate (MAL) have been used to induce experimental glomerular proteinuria and tubular disease, respectively. Current studies show that PAN caused a massive loss of albumin in the urine while not affecting the excretion of the smaller, sex-dependent alpha 2 mu-globulin. On the other hand, MAL which inhibits the reabsorption of proteins, increased the loss of both alpha 2 mu and albumin. Both nephrotoxic agents increased the excretion of albumin when administered to female rats. MAL-induced proteinuria was used as a direct measure of the renal load for alpha 2 mu and albumin. Renal loads and excretion of alpha 2 mu and albumin were measured in male rats maintained on 0, 20, and 50% casein diets. On the protein-free diet, the excretion of both alpha 2 mu and albumin was reduced (less than 1 mg daily); their renal loads were almost totally reabsorbed. On a 50% casein diet the reabsorption of alpha 2 mu was reduced from a normal of 60% to 10% of the renal load. Thus the high protein diet increased the excretion of alpha 2 mu while having little effect on the excretion of albumin. We suggest that dietary protein exerts two levels of control on the excretion of protein in the urine of the adult male rat. Protein-deficient diets stimulate the general reabsorption of proteins thereby minimizing the excretion of alpha 2 mu and albumin. High protein diets appear to reduce selectively the reabsorption of alpha 2 mu-globulin, thereby increasing its excretion in the urine.

Topics: Albumins; Albuminuria; Alpha-Globulins; Animals; Dietary Proteins; Disease Models, Animal; Female; Male; Maleates; Proteinuria; Puromycin; Puromycin Aminonucleoside; Rats; Rats, Inbred Strains

Topics: Glycosuria; Histocytochemistry; Kidney; Kidney Tubules; Maleates; Polyuria; Proteinuria; Rats; Renal Aminoacidurias; Research; Succinate Dehydrogenase; Sulfhydryl Compounds; Toxicology; Urine