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S V Shah

Publications and source records attributed to S V Shah.

At least 73 records · Page 4Linked to original sources
PubMed1990

Effects of probucol on renal function in rats with bilateral ureteral obstruction.

To ascertain the potential role of reactive oxygen metabolites in the pathophysiology of obstructive uropathy, we examined the effect of probucol, an antioxidant agent, on renal function in normal rats and rats with unilateral release of bilateral ureteral obstruction (BUO) of 24 hours duration. Rats were fed either a standard diet or a standard diet containing one percent probucol for two weeks prior to study. Probucol lowered serum cholesterol in both normal and BUO rats. Probucol did not significantly affect renal function in normal rats. BUO rats given probucol had greater inulin and PAH clearances at three to five hours and three days following release of BUO than rats with BUO not given probucol. Kidneys from obstructed rats had higher levels of malondialdehyde, an index of lipid peroxidation, a greater number of leukocytes in the cortex, decreased levels of reduced glutathione and increased levels of oxidized glutathione. Renal cortex from obstructed rats treated with probucol had significantly higher levels of reduced glutathione than kidneys of obstructed rats not given probucol. A decrease in cholesterol, using another lipid-lowering agent, lovastatin, did not modify renal function in rats with BUO. The data can be interpreted to indicate a role for reactive oxygen species in the pathophysiology of obstructive nephropathy. The improved renal function seen in probucol-treated rats with BUO may be due to an effect of this agent in affecting accumulation of reactive oxygen metabolites and/or decreasing the number of leukocytes infiltrating the renal cortex.

Animals↗
PubMed1990

Reactive oxygen metabolites in endotoxin-induced acute renal failure in rats.

Based on recent reports that reactive oxygen metabolites may play a role in endotoxin-induced injury in other tissues, we postulated that reactive oxygen metabolites may be important mediators of endotoxin-induced acute renal failure. Superoxide dismutase, a scavenger of superoxide, or catalase, which destroys hydrogen peroxide, did not protect against endotoxin-induced renal failure. Similarly, neither the hydroxyl radical scavenger dimethylthiourea nor the iron chelator deferoxamine (which presumably would act by preventing the generation of hydroxyl radical via the iron-catalyzed Haber-Weiss reaction) prevented the endotoxin-induced fall in renal function. In separate experiments, we found no increase in renal cortical lipid peroxidation (a marker of reactive oxygen metabolite-mediated tissue injury) in endotoxin-treated rats, providing further evidence against a role for reactive oxygen metabolites in endotoxin-induced renal injury. Finally, using the aminotriazole-induced inhibition of catalase (a measure of in vivo changes in the hydrogen peroxide generation) we found no evidence of enhanced hydrogen peroxide generation in the renal cortex in endotoxin-treated rats. Taken together, the data from these three separate experimental approaches suggest that reactive oxygen metabolites are not important mediators of endotoxin-induced acute renal failure.

Acute Kidney Injury↗
PubMed1989

Effect of thrombin on cyclic AMP content in glomeruli isolated from rat kidney.

Localized thrombin-mediated intravascular coagulation has been implicated as an important pathogenetic factor in a variety of glomerular and vascular diseases of the kidney. Recent studies indicate that glomerular function is affected by several hormonal agents which alter the cyclic AMP or cyclic GMP content in the glomeruli. Although thrombin has been shown to affect several metabolic processes in other cellular systems the possibility that thrombin may cause a reduction in glomerular function by altering cyclic nucleotide metabolism has not been previously considered. We therefore examined the effect of thrombin on the cyclic AMP and cyclic GMP content in glomeruli isolated from rat renal cortex. Thrombin caused a dose dependent (0.01 to 1 U/ml) increase in the cyclic AMP content in the glomeruli but had no effect on the cyclic GMP content. The effect was first observed at 30 seconds and reached a peak at five minutes. Tubules isolated from the same rats had no response to thrombin. The glomerular cyclic AMP response to thrombin inactivated with diisopropylfluorophosphate was markedly impaired, indicating the requirement for the protease activity of thrombin for the observed effect. Thrombin did not affect the cyclic AMP phosphodiesterase activity in glomeruli. Thrombin-mediated increase in glomerular cyclic AMP may play an important role in the reduction in glomerular function that is observed in a variety of glomerular and vascular renal diseases in which intravascular coagulation plays a prominent role.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1989

In vivo generation of hydrogen peroxide by rat kidney cortex and glomeruli.

The purpose of this study was to demonstrate in vivo generation of hydrogen peroxide by rat renal cortex and glomeruli. Aminotriazole irreversibly inactivates catalase only in the presence of hydrogen peroxide, and previous studies have shown that aminotriazole-mediated inhibition of catalase is a measure of in vivo changes in the hydrogen peroxide generation. Aminotriazole injected intraperitoneally caused a dose-dependent (0.1-1 g/kg) and a time-dependent (15, 30, 60, 90, 120 min) inhibition of the catalase activity in renal cortex. We confirmed that catalase inactivation by aminotriazole was due to formation of a catalase-hydrogen peroxide intermediate (compound I) because catalase inactivation was prevented by ethanol (2 g/kg), a competitive substrate for compound I. The specific activity of catalase in the glomeruli [0.27 +/- 0.026 k/mg protein (where k is the first-order reaction rate constant), n = 5] was significantly lower than the specific activity in the tubules (1.04 +/- 0.15 k/mg protein, n = 5) obtained from the same rats. The residual catalase activity (RCA) in the glomeruli (0.05 +/- 0.01 k/mg protein) was 19% of control values at 90 min after aminotriazole injection (1 g/kg). Taken together these data provide evidence for in vivo generation of hydrogen peroxide by rat renal cortex and glomeruli under normal conditions. Aminotriazole-mediated inhibition of catalase has been used in previous studies as a measure of in vivo changes in the hydrogen peroxide generation.(ABSTRACT TRUNCATED AT 250 WORDS)

Amitrole↗
PubMed1989

Enhanced in vivo H2O2 generation by rat kidney in glycerol-induced renal failure.

Aminotriazole-mediated inhibition of catalase has been used in previous studies as a measure of in vivo changes in the hydrogen peroxide generation. Using this method, we found a significantly higher inhibition of renal catalase activity at various time points (30, 60, and 90 min) in glycerol-treated rats (a well-established model for myoglobinuric acute renal failure) compared with rats treated with aminotriazole alone. The greater inhibition in the glycerol-treated group was not due to differences in aminotriazole levels. We confirmed that catalase inactivation by aminotriazole was due to formation of catalase-hydrogen peroxide intermediate (compound I) because catalase inactivation was prevented by ethanol, a competitive substrate for compound I. There were no significant differences in the aminotriazole-induced inhibition of renal cortical catalase activity in control and uranyl nitrate-treated rats, suggesting that there was no enhanced generation of hydrogen peroxide in this model of acute renal failure. Taken together, these data provide evidence for enhanced generation of hydrogen peroxide in glycerol-induced acute renal failure and suggest that the enhanced generation of hydrogen peroxide in the glycerol-induced acute renal failure is not a result of nonspecific response to tissue injury.

Acute Kidney Injury↗
PubMed1989

Bombay experience in intensive respiratory care over 6 years.

The experience of the intensive respiratory care in 930 cases treated from 1983 for 4 years and in 404 cases over the next 2 years is reported. The background operational problems are stressed. Those between age 10 and 50 years did significantly better (p less than 0.05). The survival over the first 4 years in IPPR cases was 16.3% and in non IPPR group 71.8%; over the next 2 years, the former group, survival was 32.4 and 36.3%. The survival in asthmatic patients was high (76%). In cases with organophosphorus poisoning (without IPPR), survival was 81% while in IPPR group it was 29%. In 1988, the results in this group were better due to more aggressive management. In autopsy data on 85 cases, infection was not a major feature in those dying within 24 hours. The survival in COPD cases showed significant relation to age (p less than 0.05), initial arterial pO2 below 60 mm (p less than 0.01) and arterial pH below 7.3 (p less than 0.01). In cases with pneumonia (also asthma) younger cases did better (p less than 0.05) as also those with pneumonia and initial pO2 above 60 mm (p less than 0.01) and pH above 7.3 (p less than 0.001). When pneumonia was community acquired, survival (64.8%) was better than when it was hospital acquired (24%; p less than 0.01). Only the need for IPPR affected survival in trauma group. The major cause of death was infection with Klebsiella, Pseudomonas, Staphylococci and other gram--ve organisms. It is concluded that with proper planning and training, the IRCU does provide a useful mode of treatment in selected patients with respiratory problems.

Adolescent↗
PubMed1988

The cysteine proteinase inhibitor, E-64, reduces proteinuria in an experimental model of glomerulonephritis.

Proteinuria is a major manifestation of glomerular disease (glomerulonephritis, GN). We examined the effect of trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane (E-64), a specific and irreversible cysteine proteinase inhibitor, on urinary protein excretion in a complement- and neutrophil-independent model of antiglomerular basement membrane (GBM) antibody disease. A single injection of rabbit antirat-GBM IgG produced a marked increase in urinary protein excretion 24hr after injection. In two separate studies using different pools of antiGBM IgG, administration of E-64 (5mg every 6h starting 2hr prior to induction of GN) reduced proteinuria (-45 +/- 7%, and -41 +/- 14%, Mean +/- SEM, n = 6; P less than 0.001) in the 24 hour period following induction of the disease. This reduction in urinary protein excretion was accompanied by a marked decrease in the specific activity of the cysteine proteinases cathepsins B and L in glomeruli (B: -97%; L: -84%) and renal cortex (B: -87%; L: -75%) isolated from the same E-64-treated rats compared to same saline-treated controls. These data, combined with the specificity of E-64 for cysteine proteinases, suggest a potential role for cysteine proteinases in the increased GBM permeability and proteinuria in this experimental model of glomerular disease.

Animals↗
PubMed1988

Degradation of glomerular basement membrane by purified mammalian metalloproteinases.

Neutral metalloproteinases degrade components of the extracellular matrix, including collagen types I-V, fibronectin, laminin and proteoglycan. However, their ability to degrade intact glomerular basement membrane (GBM) has not previously been investigated. Incubation of [3H]GBM (50,000 c.p.m.; pH 7.5; 24 h at 37 degrees C) with purified gelatinase or stromelysin (2 units) resulted in significant GBM degradation: gelatinase, 46 +/- 2.2; stromelysin, 59 +/- 5.8 (means +/- S.E.M.; percentage release of non-sedimentable radioactivity; n = 4). In contrast, 2 units of collagenase released only 5.6 +/- 0.52% (n = 3) of the [3H]GBM radioactivity compared with 2.0 +/- 0.15% (n = 7) released from [3H]GBM incubated alone. Sephadex G-200 gel chromatography of supernatants obtained from incubations of [3H]GBM with either gelatinase or stromelysin confirmed the ability of these enzymes to degrade GBM and revealed both high-(800,000) and relatively low-(less than 20,000) Mr degradation products for both enzymes. GBM degradation by gelatinase and stromelysin was dose-dependent (range 0.02-2.0 units), near maximal between pH 6.0 and 8.6, and was completely inhibited (greater than 95%) by 2 mM-o-phenanthroline. Collagenase (2 units) did not enhance the degradation of GBM by either gelatinase (0.02 or 0.2 unit) or stromelysin (0.02 or 0.2 unit). Our results indicate that metalloproteinase-mediated GBM degradation by neutrophils and glomeruli may be attributable to gelatinase (neutrophils) and/or stromelysin (glomeruli) and suggest an important role for these proteinases in glomerular pathophysiology.

Animals↗
PubMed1988

Evidence suggesting a role for hydroxyl radical in puromycin aminonucleoside-induced proteinuria.

A single intravenous injection of puromycin aminonucleoside (PAN) results in marked proteinuria and glomerular morphological changes that are similar to minimal change disease in humans. We examined the effect of hydroxyl radical scavengers and an iron chelator on PAN-induced proteinuria. PAN in a dose of 5 mg/100 g body wt significantly increased urinary protein by day 5 (saline: 15 +/- 2, N = 24: PAN: 63 +/- 17, N = 23, P less than 0.001); the proteinuria rapidly increased thereafter, reaching 216 +/- 34, N = 23 by day 7. Concurrent administration of hydroxyl radical scavengers dimethylthiourea, (DMTU 500 mg/kg followed by 125 mg/kg i.p. twice a day) and sodium benzoate (BENZ, 150 mg/kg followed by 125 mg/kg i.p. twice a day) starting the evening before PAN injection markedly reduced proteinuria throughout the course of the study (urinary protein, mg/24 hours on day 7, mean +/- SEM: PAN: 229 +/- 45, N = 15; PAN + DMTU: 30 +/- 5, N = 18; PAN + BENZ: 80 +/- 18, N = 16. Because of the participation of iron in biological systems to generate hydroxyl radical, we also examined the effect of deferoxamine (DFO, 30 mg/day), an iron chelator, on the PAN-induced proteinuria. Concurrent administration of DFO was also protective. In a second series of experiments, DMTU and DFO (administered as described above and then for two additional days after the PAN) provided marked protection even when they were stopped prior to the onset of proteinuria. The protective effects of two hydroxyl radical scavengers and iron chelator implicate an important role for hydroxyl radical in PAN-induced nephrotic syndrome.

Animals↗
PubMed1988

Evidence suggesting a role for hydroxyl radical in passive Heymann nephritis in rats.

We examined the effect of scavengers of reactive oxygen metabolites on proteinuria in the passive Heymann nephritis model of membranous nephropathy. Passive Heymann nephritis was induced by a single intravenous injection of anti-Fx1A IgG in a dose of 10 mg/100 g body weight. Superoxide dismutase, a scavenger of superoxide or catalase which destroys hydrogen peroxide, did not affect the proteinuria. In contrast, dimethylthiourea (DMTU, 500 mg/kg followed by 125 mg/kg ip twice a day), a scavenger of hydroxyl radical, markedly reduced the proteinuria (day 5: anti-Fx1A 53 +/- 13, n = 18; anti-Fx1A + DMTU, 21 +/- 6 mg/24 h, n = 15, P less than 0.001). Experiments with 125I-labeled anti-Fx1A antibody demonstrated that DMTU did not affect the amount of antibody deposited in the kidney. Semiquantitative estimation of IgG and complement deposition in the kidney showed no differences between the DMTU-treated and control rats. A second hydroxyl radical scavenger, sodium benzoate (150 mg/kg ip twice a day), also resulted in marked reduction in proteinuria (day 5: anti-Fx1A 56 +/- 7, n = 9; anti-Fx1A + benzoate, 14 +/- 4 mg/24 h, n = 8, P less than 0.01). Because of the participation of iron in biological systems to generate hydroxyl radical, we also examined the effect of deferoxamine (DFO, 35 mg/day), an iron chelator, on the anti-Fx1A-induced proteinuria. There was a significant reduction in proteinuria in rats treated concurrently with DFO (day 5: anti-Fx1A 67 +/- 13, n = 15; anti-Fx1A + DFO, 29 +/- 4 mg/24 h, n = 15, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Evidence suggesting a role for hydroxyl radical in glycerol-induced acute renal failure.

Reactive oxygen metabolites, in particular hydroxyl radical, have been shown to be important mediators of tissue injury in several models of acute renal failure. The aim of the present study was to examine the role of hydroxyl radical in glycerol-induced acute renal failure, a model for myoglobinuric renal injury. Rats injected with glycerol alone (8 mg/kg im following dehydration for 24 h) developed significant renal failure compared with dehydrated controls. Rats treated with glycerol and a hydroxyl radical scavenger, dimethylthiourea (DMTU), had significantly lower blood urea nitrogen (BUN) and creatinine. In contrast, urea, which is chemically similar to DMTU but is not a hydroxyl radical scavenger, provided no protection. In addition, DMTU prevented the glycerol-induced rise in renal cortical malondialdehyde content (a measure of lipid peroxidation that serves as a marker of free radical-mediated tissue injury). A second hydroxyl radical scavenger, sodium benzoate, had a similar protective effect on renal function (as measured by both BUN and creatinine). Because the generation of hydroxyl radical in biological systems requires the presence of a trace metal such as iron, we also examined the effect of the iron chelator, deferoxamine on glycerol-induced renal failure. Deferoxamine was also protective. The interventional agents were also associated with a marked reduction in histological evidence of renal damage. The protective effects of two hydroxyl radical scavengers as well as an iron chelator implicate a role for hydroxyl radical in glycerol-induced acute renal failure.

Acute Kidney Injury↗
PubMed1988

Evidence suggesting a role for hydroxyl radical in gentamicin-induced acute renal failure in rats.

The protective effect of hydroxyl radical scavengers and iron chelators has strongly implicated the hydroxyl radical in several models of tissue injury. Based on in vitro studies showing gentamicin-enhanced generation of reactive oxygen metabolites in renal cortical mitochondria, we examined the effect of hydroxyl radical scavengers and iron chelators in gentamicin-induced acute renal failure. Rats treated with gentamicin (G) alone (100 mg/kg, s.c. x 8 d) developed advanced renal failure (BUN 215 +/- 30 mg/dl) compared to saline-treated controls (BUN 16 +/- 1 mg/dl, P less than 0.001). In contrast, rats treated with gentamicin and either dimethylthiourea (DMTU, an hydroxyl radical scavenger, 125 mg/kg, i.p. twice a day) or deferoxamine (DFO, an iron chelator, 20 mg/day by osmotic pump) had significantly lower BUN (G + DMTU 48.8 +/- 8 mg/dl, P less than 0.001, n = 8; G + DFO 30 +/- 7 mg/dl, P less than 0.001, n = 8). In separate experiments, treatment with two other hydroxyl radical scavengers (dimethyl sulfoxide or sodium benzoate) and a second iron chelator (2,3,dihydroxybenzoic acid) had a similar protective effect on renal function (as measured by both BUN and creatinine). In addition, histological evidence of damage was markedly reduced by the interventional agents. Finally, concurrent treatment with DMTU prevented the gentamicin induced increase in renal cortical malondialdehyde content (G: 4.4 +/- 0.2 nmol/mg; G + DMTU: 3.1 +/- 0.2 nmol/mg, P less than 0.0001, n = 8) suggesting that the protective effect of DMTU was related to free radical mechanisms rather than to some other effect. Taken together, these data strongly support a role for hydroxyl radical or a similar oxidant in gentamicin-induced acute renal failure.

Acute Kidney Injury↗
PubMed1987

The role of aspartic and cysteine proteinases in albumin degradation by rat kidney cortical lysosomes.

We have investigated the degradation of 125I-labeled bovine serum albumin by lysates of rat kidney cortical lysosomes. Maximal degradation of albumin occurred at pH 3.5-4.2, with approximately 70% of the maximal rate occurring at pH 5.0. Degradation was proportional to lysosomal protein concentration (range 100-600 micrograms) and time of incubation (1-5 h). Dithioerythritol (2 mM) stimulated albumin degradation 5- to 10-fold. Albumin degradation was not inhibited by phenylmethanesulfonyl fluoride (1 mM) or EDTA (5 mM), indicating that neither serine nor metalloproteinases are involved to a significant extent. Pepstatin (5 micrograms/ml), an inhibitor of aspartic proteinases, inhibited albumin degradation by approximately 50%. Leupeptin (10 microM) and N-ethylmaleimide (10 mM), inhibitors of cysteine proteinases, decreased albumin degradation by 34 and 65%, respectively. Combinations of aspartic and cysteine proteinase inhibitors produced nearly complete inhibition of albumin degradation. Taken together, these data indicate that aspartic and cysteine proteinases are primarily responsible for albumin degradation by renal cortical lysosomes under these conditions. In keeping with the above data, we have measured high activities of the cysteine proteinases, cathepsins B, H, and L, in cortical tubules, the major site of renal protein degradation. Using the peptidyl 7-amino-4-methylcoumarin (NHMec) substrates (Z-Arg-Arg-NHMec, for cathepsin B; Arg-NHMec for cathepsin H; and Z-Phe-Phe-CHN2-inhibitable hydrolysis of Z-Phe-Arg-NHMec corrected for inhibition of cathepsin B activity for cathepsin L) values obtained were (means +/- SE, mU/mg protein, 1 mU = production of 1 nM product/min, n = 6): cathepsin B, 2.1 +/- 0.34; cathepsin H, 1.35 +/- 0.19; cathepsin L, 14.49 +/- 1.26. In comparison, the activities of cathepsins B, H, and L in liver were: 0.56 +/- 0.03, 0.28 +/- 0.04, and 1.27 +/- 0.16, respectively.

Animals↗