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Biomedical subjects

M Brezis

Publications and source records attributed to M Brezis.

At least 37 records · Page 2Linked to original sources
PubMed1998

The endogenous insulin-like growth factor system in radiocontrast nephropathy.

The response of insulin-like growth factor (IGF) I in acute renal failure was evaluated in a model of radiocontrast nephropathy associated with selective necrosis of medullary thick ascending limbs. In brief, rats were administered radiocontrast medium or vehicle injections for controls after combined inhibition of prostanoids and nitric oxide. Twenty-four hours after the insult, tissue mRNAs for IGF-I, the IGF-I receptor, and IGF-binding proteins (IGFBP) 1 and 3 were assayed in cortex, medulla, and liver by solution hybridization-RNase protection assay, and IGFBPs were measured in serum and tissue by Western ligand blotting. Cortical IGF-1 increased, whereas medullary IGF-I mRNA decreased. Renal IGFBPs decreased, whereas IGFBP-1 mRNA increased. The IGF system in the liver was unchanged. We conclude that general changes in renal IGFBPs in this experimental model of acute renal failure might increase the level of cortical IGF-I in a way that could modulate medullary recovery.

Acute Kidney Injury↗
PubMed1997

Renal microcirculation and tissue damage during acute ureteral obstruction in the rat: effect of saline infusion, indomethacin and radiocontrast.

Radiocontrast agents and nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the diagnosis and treatment of renal colic. We studied their impact during unilateral acute urinary outflow obstruction upon renal microcirculation and parenchymal integrity. Laser-Doppler and ultrasonic regional flow measurements demonstrated selective decline of outer medullary blood flow by 23 +/- 2% during an acute increase of intra-pelvic pressure to 50 to 55 cm H2O (N = 28, X +/- SEM, P < 0.01). In rats preconditioned with indomethacin, this manipulation reduced medullary blood flow by 50 +/- 4% (N = 16, P < 0.01 vs. obstruction alone), with cortical and total renal blood flow declining by 18 +/- 4% and 16 +/- 2%, respectively (P < 0.01). Unilateral obstruction alone for 24 hours in intact rats resulted in injury (hemorrhage and necrosis) to the papilla and fornix (formed laterally by inner stripe and medially by the inner medulla). These changes were detected as early as 30 minutes after ureteral ligature by staining for fragmented nuclear DNA (TUNEL). Mild damage of thick ascending limbs (mTALs) was associated with substantial medial fornix injury. Indomethacin markedly increased mTAL injury in obstructed kidneys, but attenuated inner medullary damage, both in the medial border of the urinary space and at the papilla. This latter protective effect, probably mediated by the decrease in intrapelvic pressure, was blunted by concomitant intravenous fluid load. Contrast media (iothalamate) and L-NAME (N omega nitro-L-arginine methyl ester) both augmented inner stripe and inner medullary damage in hydronephrotic kidneys. In rats concomitantly subjected to radiocontrast, indomethacin and L-NAME (an acute renal failure protocol, J Clin Invest 94:1069, 1994), unilateral obstruction augmented inner stripe hypoxic damage (65 +/- 6% vs. 24 +/- 11% of mTALs in contralateral kidneys, N = 7, P < 0.01). Injury was maximal at the fornix (93 +/- 6% vs. 39 +/- 14% of mTALs in the mid-inner stripe, P < 0.01) and extended to the outer stripe and medullary rays. Thus, in the rat acute ureteral obstruction alters medullary blood flow and within 24 hours produces medullary damage in both forniceal and inner medullary locations, that is exacerbated by concomitant measures which limit medullary oxygenation. Contrast studies, forced hydration and NSAIDs for renal colic are potentially harmful and their use should be re-evaluated.

Acute Disease↗
PubMed1997

The effect of ketotifen on nitric oxide synthase activity.

1. We studied the effect of ketotifen, a second generation H1-receptor antagonist on nitric oxide synthase (NOS) activity in colonic mucosa and in renal tissues, and on rat renal haemodynamics in vivo. 2. Ketotifen (100 micrograms ml-1) increased human colonic NOS activity from 3.7 +/- 0.6 to 14.5 +/- 1.3 nmol g-1 min-1 (P < 0.005, ANOVA). In rat renal cortical and medullary tissues ketotifen increased NOS activity by 55% and 86%, respectively (P < 0.001). The stimulation of NOS activity was attenuated by NADPH deletion and by the addition of N omega nitro-L-arginine methyl ester (L-NAME) or aminoguanidine, but not by [Ca2+] deprivation. NOS activity was unaffected by two other H1-antagonists, diphenhydramine and astemizole, or by the structurally related cyproheptadine. Renal cortical NOS activity was also significantly stimulated 90 min after intravenous administration of ketotifen to anaesthetized rats. 3. Ketotifen administration to anaesthetized rats induced modest declines in blood pressure and reduced total renal, cortical and outer medullary vascular resistance. This is in contrast to diphenhydramine, which did not induce renal vasodilatation. 4. We conclude that ketotifen stimulates NOS activity by mechanisms other than H1-receptor antagonism. The association of this effect with therapeutic characteristics of ketotifen and the clinical implications of these findings are yet to be defined.

Animals↗
PubMed1997

Medullary injury in the ageing rat kidney: functional-morphometric correlations.

Urinary concentrating ability decreases with age in both humans and animals. This phenomenon is not yet clearly explained or corroborated by morphological findings, often focused on glomerular changes. In rats aged 5-22 months, semi-quantitative and quantitative morphometric analysis was performed to score cortical and medullary changes. Morphological-data were related to renal functional parameters. Three stages of tubulo-interstitial injury were observed: minimal findings (stage I); mild fibrosis with atrophy and casts in medullary thick ascending limbs (stage II): extensive fibrosis and atrophy with large cast formation (stage III). Maximal urinary osmolality decreased in correlation with the stage of tubulointerstitial injury (r = -0.8, P < 0.001), from 3735 mosmol L-1 at stage I to 2807 at stage II and 1567 at stage III. A dissociation was observed in the rate of progression with age between tubulointerstitial injury and glomerular sclerosis. Whereas sclerosis was observed in only 2-3% of glomeruli at both stages I and II of tubulointerstitial injury, damage to thick ascending limbs significantly increased from 2% of tubules at stage 1 to 11% at stage II (P < 0.002). At stage III, both extensive glomerular sclerosis (53%) and tubular injury (32%) were present. Uninephrectomy accelerated both morphological injury and functional compromise. We conclude that, in the early stages of renal ageing, injury to medullary tubules may be more prevalent than injury to glomeruli and could be responsible for the reduction in concentrating ability.

Aging↗
PubMed1997

Shiga toxin induces medullary tubular injury in isolated perfused rat kidneys.

To investigate the potential direct nephrotoxicity of Shiga toxin, a putative mediator for hemolytic uremic syndrome, purified toxin (10(-11) M) was added to isolated rat kidneys perfused for 160 min with a Krebs-Henseleit acellular medium enriched with albumin and amino acids. Kidney function and morphology were examined after perfusion with the Shiga toxin vs controls. Shiga toxin did not significantly alter renal perfusion flow, glomerular filtration rate, or tubular sodium reabsorption, but it significantly increased urinary protein excretion (from 61 +/- 23 to 169 +/- 28 microg/min, P < 0.01). On renal morphologic study, Shiga toxin did not induce gross glomerular damage but increased markedly the injury to the medullary thick ascending limbs. In conclusion, Shiga toxin is toxic to rat kidneys ex vivo and in the absence of platelets. Renal damage is manifested by proteinuria and medullary tubular injury. The distribution of this injury suggests a possible synergism between local medullary hypoxia and the toxic tubular or endothelial effects of the toxin. These effects may play a pathogenic role in the tubulo-interstitial injury observed in hemolytic uremic syndrome associated with severe renal failure.

Animals↗
PubMed1996

Myoglobinuric acute renal failure in the rat: a role for medullary hypoperfusion, hypoxia, and tubular obstruction.

Myoglobin induces renal injury by mechanisms that remain incompletely defined. In this study, the effects of myoglobin upon renal microcirculation, oxygenation, morphology, and function were investigated in anesthetized rats, and the contribution of coexisting perturbations to myoglobin nephrotoxicity were evaluated. Myoglobin infusion (3.3 mg/min) reduced outer medullary blood flow and Po2, whereas renal blood flow and cortical Po2 were unaffected. Myoglobin infusion (38 mg/100 g weight over 45 min) induced renal failure associated with collecting duct and medullary thick ascending limb dilation and casts, with focal tubular damage, confined mainly to the superficial cortex. Preconditioning with indomethacin, I-N-monomethyl arginine, and theophylline reduced cortical superficial damage but enhanced injury within the inner stripe of the outer medulla and in medullary rays, the zones of lowest O2 supply. In preconditioned animals, tubulorrhexis was primarily observed in collecting ducts transversing the inner stripe, and was remarkably reminiscent of human descriptions (J. Oliver et al., J Clin Invest 1951; 30: 1307-1440). Deterioration in kidney function closely correlated with morphologic features of both tubular obstruction and necrosis. In conclusion, medullary vasoconstriction and intrarenal hypoxia may play a role in myoglobin-induced renal failure. The deterioration in kidney function appears to reflect the combined effects of cortical damage, medullary hypoxic injury, and tubular obstruction.

Acute Kidney Injury↗
PubMed1995

Rapid DNA fragmentation from hypoxia along the thick ascending limb of rat kidneys.

Extensive DNA fragmentation, a marker for programmed cell death, was selectively and rapidly induced by hypoxia in the thick ascending limbs of rat kidneys. In isolated perfused kidneys, DNA breaks were present in medullary tubules as early as after 10 minutes of local hypoxia and were prevented by reduction of metabolic work. In a model of radiocontrast-induced acute renal failure, DNA breaks were detected selectively along thick ascending limbs as early as 15 minutes following insult, preceding overt morphological damage. Hypoxia induces rapid DNA fragmentation along thick ascending limbs, where programmed cell death could play an important role in nephron injury and kidney failure.

Acute Kidney Injury↗