Binding of an aldose reductase inhibitor to renal glomeruli

Cohen, Morrel H.; Klepser, Henry

doi:10.1016/0006-291x(85)90184-6

Cited by 11 publications

(4 citation statements)

References 17 publications

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“…This effect is rapid and occurs within minutes after incubation of glomerular membranes with the hormone or with the drug. This finding supports the notion suggested by the results of previous experiments demonstrating that [ 3 H]sorbinil binds in a dose-dependent and saturable manner to crude membranes prepared from isolated rat renal glomeruli (19) and that the compound has an effect on membrane-associated complexes that is concomitant to, or independent of, its aldose reductase-inhibiting property. Several hypotheses have been advanced to explain the ability of sorbinil in vivo to restore Na + -K + -ATPase activity in diabetic peripheral nerve and glomeruli.…”

Section: Discussionsupporting

confidence: 91%

“…These experiments were considered of interest in view of the central position that the ability of sorbinil to restore Na + -K + -ATPase activity in vivo occupies in the interpretive scheme that links associated changes in sorbitol, myo-inositol, and Na + -K + -ATPase to enhanced polyol-pathway activity (11,18). That sorbinil might have a direct effect on the Na + pump was suggested by its lipophilicity, its influence on processes related to membrane-associated complexes such as ion transport and impulse propagation, and its ability to bind to cell membranes (19). Acute diabetes is <18 days duration and includes corresponding age-matched control rats; n = 4 in each group.…”

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confidence: 99%

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Glomerular Na+-K+-ATPase Activity in Acute and Chronic Diabetes and With Aldose Reductase Inhibition

Cohen

Klepser²

1988

Diabetes

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Sorbitol accumulation, myo-inositol depletion, and reduced Na+-K+-ATPase activity have been identified in experimental diabetes in several tissues in which diabetic complications occur. However, a reduction in renal Na+-K+-ATPase activity has not been universally reported, prompting us to examine the influence of diabetes duration on the activity of this enzyme complex in isolated glomeruli. Additionally, we examined the ability of the aldose reductase inhibitor sorbinil to directly stimulate glomerular Na+-K+-ATPase activity in vitro, an area of interest in view of the central position that the ability of sorbinil to restore Na+-K+-ATPase activity in vivo occupies in the interpretive scheme that links associated changes in sorbitol, myo-inositol, and Na+-K+-ATPase to enhanced polyol-pathway activity. Glomerular Na+-K+-ATPase activity was significantly decreased in rats with acute (less than 18 days) streptozocin-induced diabetes but was significantly greater than control values in rats with more chronic (greater than 32 days) diabetes. In vitro addition of sorbinil (1 x 10(-7) M) directly stimulated Na+-K+-ATPase in control (0.627 +/- 0.090 vs. 0.843 +/- 0.098 mumol P1.mg-1.min-1) but not diabetic glomeruli. These results indicate that the time of examination after induction of diabetes critically influences glomerular Na+-K+-ATPase activity and suggest that sorbinil, at least in normal glomerular tissue, has a membrane-associated effect that may be independent of its aldose reductase-inhibiting property.

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

Glomerular Na+-K+-ATPase Activity in Acute and Chronic Diabetes and With Aldose Reductase Inhibition

Cohen

Klepser²

1988

Diabetes

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“…However, the mechanism by which sorbinil prevents the fall in inositol is not known (2). Sorbinil has been shown to bind to glomeruli (32) and thus might influence membrane transport through mechanisms that do not involve aldose reductase activity. In this regard, we have been unable to demonstrate an increase in glomerular sorbitol content at 1-2 wk after induction of diabetes, at a time when inositol content was reduced (unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C is activated in glomeruli from streptozotocin diabetic rats. Possible mediation by glucose.

Craven¹,

DeRubertis²

1989

J. Clin. Invest.

321

170

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Glomerular inositol content and the turnover of polyphosphoinositides was reduced by 58% in 1-2 wk streptozotocin diabetic rats. Addition of inositol to the incubation medium increased polyphosphoinositide turnover in glomeruli from diabetic rats to control values. Despite the reduction in inositol content and polyphosphoinositide turnover, protein kinase C was activated in glomeruli from diabetic rats, as assessed by an increase in the percentage of enzyme activity associated with the particulate cell fraction. Total protein kinase C activity was not different between glomeruli from control and diabetic rats. Treatment of diabetic rats with insulin to achieve near euglycemia prevented the increase in particulate protein kinase C. Moreover, incubation of glomeruli from control rats with glucose (100-1,000 mg/dl) resulted in a progressive increase in labeled diacylglycerol production and in the percentage of protein kinase C activity which was associated with the particulate fraction. These results support a role for hyperglycemia per se in the enhanced state of activation of protein kinase C seen in glomeruli from diabetic rats. Glucose did not appear to increase diacylglycerol by stimulating inositol phospholipid hydrolysis in glomeruli. Other pathways for diacylglycerol production, including de novo synthesis and phospholipase C mediated hydrolysis of phosphatidylcholine or phosphatidylinositol-glycan are not excluded.

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“…In addition, the lipid solubility of sorbinil suggests the possibility of an interaction with plasma membrane-associated phospholipid components and/or phospholipid-related cell cycles. In fact, binding of sorbinil to cell membranes in another tissue has been demonstrated (22). Thus, the impact of sorbinil in vivo on the decreased erythrocyte deformability associated with diabetes may partly relate to an influence on physicochemical properties of the RBC membrane, either as a result of its action as an aldose reductase inhibitor or as an independent effect.…”

Section: Discussionmentioning

confidence: 99%

Sorbinil Partially Prevents Decreased Erythrocyte Deformability in Experimental Diabetes Mellitus

et al. 1987

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The ability of red blood cells (RBCs) to undergo an adaptation in shape that permits passage through the smallest vessels is reportedly impaired in diabetes. Several hypotheses have been proposed to explain decreased erythrocyte deformability, which has been implicated in the pathogenesis of microvascular complications, but the mechanisms responsible for this change have not been clearly delineated. In view of the fact that sorbitol accumulates in RBCs in diabetes and the postulate that increased sorbitol could alter deformability properties, we examined the influence of the aldose reductase inhibitor sorbinil on erythrocyte deformability. Erythrocyte deformability, determined as the volume of RBCs (VRBC) filtered per minute through 4.7-micron pore size filters, was significantly reduced in samples from diabetic rats compared with samples from controls (0.76 +/- 0.03 vs. 0.97 +/- .02 ml RBC/min; P less than .001). In contrast, deformability of RBCs from diabetic animals treated with sorbinil was significantly greater than in untreated diabetes, although not completely normalized (0.88 +/- 0.02; P less than .01 vs. diabetic, and P less than .02 vs. control). The reduced deformability characterizing cells from diabetic rats and its partial prevention by sorbinil persisted even when RBCs were washed to eliminate hyperglycemia and hyperviscous plasma. Thus, hyperviscosity per se is not responsible for the decreased deformability, and sorbinil can partially prevent this change despite persistent hyperglycemia. This effect may derive from sorbinil's action as an aldose reductase inhibitor and/or its ability to influence physicochemical properties of the erythrocyte membrane.

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Binding of an aldose reductase inhibitor to renal glomeruli

Cited by 11 publications

References 17 publications

Glomerular Na+-K+-ATPase Activity in Acute and Chronic Diabetes and With Aldose Reductase Inhibition

Glomerular Na+-K+-ATPase Activity in Acute and Chronic Diabetes and With Aldose Reductase Inhibition

Protein kinase C is activated in glomeruli from streptozotocin diabetic rats. Possible mediation by glucose.

Sorbinil Partially Prevents Decreased Erythrocyte Deformability in Experimental Diabetes Mellitus

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