sorbinil and Diabetic-Nephropathies

Aldose reductase inhibitors impede flux of glucose through the sorbitol pathway in diabetes mellitus. They therefore reduce the accumulation of the pathway metabolites, sorbitol and fructose, reduce the impact of the flux on the cofactors used by the pathway and reduce other derived phenomena, such as osmotic stress and myo-inositol depletion. As drugs, their targets are the chronic complications of diabetes--neuropathy, retinopathy, nephropathy and vasculopathy. In experimental models there is proof of activity against biochemical, functional and structural defects in all of the involved tissues, but we await full clinical verification of this potential.

Topics: Aldehyde Reductase; Animals; Cataract; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Humans; Imidazoles; Imidazolidines

Topics: Aldehyde Reductase; Blood Glucose; Diabetes Complications; Diabetes Mellitus; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Humans; Imidazoles; Imidazolidines; L-Iditol 2-Dehydrogenase; Naphthalenes; Phthalazines; Sugar Alcohol Dehydrogenases

Topics: Aldehyde Reductase; Animals; Binding Sites; Blood Glucose; Cataract; Chemical Phenomena; Chemistry; Corneal Diseases; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Disease Models, Animal; Fluorenes; Galactose; Humans; Hydantoins; Imidazoles; Imidazolidines; Models, Molecular; Naphthalenes; Phthalazines; Rhodanine; Sorbitol; Structure-Activity Relationship; Substrate Specificity; Sugar Alcohol Dehydrogenases; Thiazolidines; Tissue Distribution

Aldose reductase inhibitors impede flux of glucose through the sorbitol pathway in diabetes mellitus. They therefore reduce the accumulation of the pathway metabolites, sorbitol and fructose, reduce the impact of the flux on the cofactors used by the pathway and reduce other derived phenomena, such as osmotic stress and myo-inositol depletion. As drugs, their targets are the chronic complications of diabetes--neuropathy, retinopathy, nephropathy and vasculopathy. In experimental models there is proof of activity against biochemical, functional and structural defects in all of the involved tissues, but we await full clinical verification of this potential.

Topics: Aldehyde Reductase; Animals; Cataract; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Humans; Imidazoles; Imidazolidines

Thickening and reduplication of the tubular basement membrane have been reported as early events in diabetic nephropathy. In this study, we have examined the polar requirements of proximal tubular cells for the d-glucose-stimulated accumulation of fibronectin and the mechanism by which this occurred, with particular emphasis on the polyol pathway.. To determine the polarity of fibronectin generation in response to glucose, LLC-PK1 cells were grown on porous tissue culture inserts. Monolayer confluence was determined by serial measurement of transepithelial resistance. Confluent cells were growth arrested by serum deprivation, and all experiments were performed under serum-free conditions.. Application of 25 mm d-glucose to either the apical or basolateral aspect of LLC-PK1 cells led to fibronectin accumulation in the basolateral compartment. This reached statistical significance 24 hours following apical addition of glucose (2.6-fold increase compared with 5 mm d-glucose, P = 0.0025, N = 6 vs. N = 4 controls) and 12 hours after the basolateral addition of glucose (2.5-fold increase compared with 5 mm d-glucose, P = 0.03, N = 6 vs. N = 4 controls). Exposure of cells to glucose at either their apical or basolateral aspect leads to accumulation of intracellular glucose and polyol pathway activation, as assessed by sorbitol accumulation. The increase in fibronectin concentration in response to glucose was inhibited by the aldose reductase inhibitor sorbinil. At a dose of 100 micron sorbinil, there was a 59% inhibition of fibronectin accumulation in response to apical glucose (P = 0.004, N = 3 sorbinil vs. N = 4 controls) and a 66% inhibition in response to basolateral glucose (P = 0.008, N = 3 sorbinil vs. N = 4 controls) 48 hours after the addition of the inhibitor. Furthermore, fibronectin accumulation was also demonstrated following both the apical and basolateral addition of 1 mm sorbitol, but not following the addition of 25 mm galactose to either aspect of the cells. Following the addition of sorbitol, there was a 2. 8-fold increase in fibronectin 48 hours after apical stimulation (P = 0.01, N = 3 treated vs. N = 4 control) and a 2.27-fold increase following basolateral stimulation (P = 0.04, N = 3 treated vs. N = 4 control) at 24 hours.. In summary, these data demonstrate that fibronectin generation in response to glucose was nonpolar in terms of application of glucose but was polar in terms of fibronectin accumulation. The mechanisms of glucose-induced modulation of fibronectin were mediated by polyol pathway activation and were more specifically related to the metabolism of sorbitol to fructose.

Topics: Aldehyde Reductase; Animals; Basement Membrane; Diabetic Nephropathies; Enzyme Inhibitors; Fibronectins; Fructose; Glucose; Humans; Imidazoles; Imidazolidines; Kidney Tubules, Proximal; LLC-PK1 Cells; Sorbitol; Swine

The effects of aldose reductase inhibition on renal function in hyperphagic diabetic rats were examined at 3 months. To prevent a high dietary protein intake from influencing renal function, protein intake in the diabetic animals was reduced to that of nondiabetic animals. To determine the influence of renal prostaglandins, clearance studies were performed before and after indomethacin infusion. Experiments were performed in uninephrectomized sorbinil-treated and -untreated streptozocin-diabetic and sorbinil-treated and -untreated control rats. Despite normalization of protein intake, the mean value of the insulin clearance (CIn, mL/min/100 g BW) was 83% greater in the untreated diabetic rats when compared to the untreated control rats (1.06 +/- 0.15 vs. 0.58 +/- 0.07; p less than 0.05). In contrast, the mean value of the CIn in the sorbinil-treated diabetic rats was significantly less than that in the untreated diabetic rats and only 38% greater than the mean value in the sorbinil-treated control rats (0.84 +/- 0.17 vs. 0.61 +/- 0.05; p less than 0.05). In a similar fashion, without sorbinil treatment the mean value of renal blood flow (RBF, mL/min/100 g BW) was greater in the diabetic than the control rats (6.58 +/- 2.03 vs. 3.70 +/- 0.68; p less than 0.05); whereas the mean values of RBF in the sorbinil-treated diabetic and control rats were not significantly different (4.75 +/- 0.73 vs. 4.17 +/- 0.64; NS). Indomethacin infusion failed to cause changes in the CIn and RBF in any group of animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldehyde Reductase; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dietary Proteins; Imidazoles; Imidazolidines; Indomethacin; Kidney; Male; Rats; Rats, Inbred Strains; Renal Circulation

1. It has been proposed that increased fructose contributes to the formation of fluorescent pigments in diabetic tissues. 2. Since the aldose reductase inhibitor sorbinil lowers glomerular fructose concentrations, we examined the effect of sorbinil on the formation of advanced glycation end products in glomerular basement membrane of streptozotocin diabetic rats. 3. Treatment with sorbinil for 30 days after induction of diabetes did not influence the increased fluorescence observed in collagen from glomerular basement membrane of untreated diabetic rats. 4. The results suggest that nonenzymatic glycation by fructose is not a major contributor to the formation of fluorescent advanced glycation end products in basement membrane in experimental diabetes.

Topics: Aldehyde Reductase; Animals; Basement Membrane; Collagen; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fructose; Glycosylation; Imidazoles; Imidazolidines; Kidney Glomerulus; Male; Rats; Spectrometry, Fluorescence

The role of polyol pathway metabolism in glomerular hyperperfusion of insulin-dependent diabetes mellitus (IDDM) was studied in rats. Streptozotocin-induced diabetic rats were fed the aldose reductase inhibitor, sorbinil (8 mg/day). Untreated diabetic rats and normal rats served as controls. All groups were fed the same diet, rationed to 20 g/day. Micropuncture, plasma renin activity (PRA), and glomerular angiotensin II (ANG II)-receptor measurements were made 7-15 days after streptozotocin injection. Untreated diabetic rats had higher than normal single-nephron filtration rate (SNGFR), plasma flow (QA), and blood flow (SNBF), and reduced afferent resistance. Glomerular ANG II-receptor sites were markedly decreased. In diabetic rats fed sorbinil SNGFR, QA, and SNBF were all lower than in untreated diabetic rats, and indistinguishable from values in normal rats. However, single-nephron filtration fraction (SNFF) rose above normal. PRA, glomerular ANG II receptors, and blood glucose were not affected by sorbinil. In normal rats fed sorbinil, SNGFR, QA, and SNBF were not significantly different than in normal rats. Our observations are consistent with the view that polyol pathway metabolism plays a role in glomerular hyperperfusion in IDDM. Inhibition of aldose reductase increased vascular smooth muscle tone at pre- and probably postglomerular sites.

Topics: Aldehyde Reductase; Animals; Blood Pressure; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Hemodynamics; Imidazoles; Imidazolidines; Kidney Glomerulus; Male; Mathematics; Models, Theoretical; Rats; Rats, Inbred Strains; Reference Values; Sugar Alcohol Dehydrogenases

We investigated the role of the aldose reductase pathway in the pathogenesis of the nephropathy of rats with sever (non-insulin-treated) streptozocin-induced diabetes of 6 mo duration. The initial experiment included four groups of rats: diabetic and control animals on a 20% protein diet, which were untreated or treated with sorbinil (an aldose reductase inhibitor). Food intake was increased by diabetes but was uninfluenced by sorbinil, whereas urinary urea nitrogen excretion was increased and body weight was decreased by both variables. Glomerular basement membrane (GBM) width was increased by diabetes and decreased by sorbinil. No other structural changes were noted. We speculated that sorbinil could have slowed the abnormal rate of GBM thickening in diabetic rats and the normal increase in GBM width in control rats by inducing a mild catabolic state. The second experiment also involved four groups of rats: diabetic and control animals on a 50% protein diet, which were untreated or treated with sorbinil. In these studies, diabetes was again associated with reduced body weight, but sorbinil had no influence on urinary urea nitrogen. Urinary albumin excretion, which was increased by diabetes, was not affected by sorbinil. GBM width was increased by diabetes, but in contrast to animals on 20% protein diets, the animals on 50% protein diets and treated with sorbinil did not have reduced GBM widths. Mesangial volume fraction was greater in diabetic animals than in controls, and sorbinil largely prevented mesangial expansion in them. Surprisingly, the control animals on the 50% protein diet and given sorbinil had increased mesangial volume fraction compared with control rats on the same diet not given the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldehyde Reductase; Animals; Basement Membrane; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dietary Proteins; Imidazoles; Imidazolidines; Kidney Cortex; Kidney Glomerulus; Male; Microscopy, Electron; Rats; Rats, Inbred Lew; Sorbitol; Streptozocin

To explore a possible link between diabetic nephropathy and the enhanced activity of the polyol pathway known to occur in diabetes, we examined several pertinent metabolic parameters in glomeruli isolated from control and streptozotocin-diabetic rats and assessed whether changes observed in diabetic glomeruli could be prevented by the oral administration of the aldose reductase inhibitor sorbinil. We found that glomerular polyol content is significantly increased in diabetes, whereas glomerular myo-inositol content is significantly reduced. The sorbitol accumulation and myo-inositol depletion were both completely prevented by sorbinil, which was given throughout the duration of diabetes. Activity of the membrane-bound sodium/potassium adenosine triphosphatase (Na-K-ATPase) was decreased in diabetic samples; this change was also completely prevented by sorbinil. Erythrocyte deformability is another factor that has been implicated in the pathogenesis of microangiopathic complications. The ability of red blood cells to undergo an adaptation in shape that permits passage through the smallest vessels is impaired in diabetes. Using blood from control, diabetic, and sorbinil-treated diabetic rats, we found that erythrocyte deformability was decreased in diabetic samples and that sorbinil treatment significantly improved this parameter. Thus, if the glomerular consequences of sorbitol accumulation, myo-inositol depletion, reduced Na-K-ATPase activity, and decreased erythrocyte deformability are pathogenetically implicated in diabetic nephropathy, the ability of sorbinil to impact on these changes suggests that it could favorably impact on the nephropathic process.

Topics: Aldehyde Reductase; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Imidazoles; Imidazolidines; Kidney Glomerulus; Rats; Sodium-Potassium-Exchanging ATPase; Sugar Alcohol Dehydrogenases

Nephropathy is a serious complication of Type I or insulin-dependent diabetes mellitus (IDDM) with a poor prognosis after the onset of proteinuria. Since aldose reductase may be implicated in the pathogenesis of proteinuria, onset and reversal studies were performed with sorbinil at a dose of 20 mg/kg to determine whether inhibition of this enzyme promoted either diminution or reversal of the appearance of urinary proteins. In the onset study, age-matched control, streptozotocin-diabetic, and sorbinil-treated diabetic rats were maintained for ten weeks; their 24-hour urine samples were analyzed weekly for volume, glucose, ketones, total protein, and individual protein components with molecular weights between 15,000 and 120,000 daltons. These last were examined by polyacrylamide gel electrophoresis and quantitated by laser densitometric analysis. Results indicated that sorbinil administered daily for ten weeks effectively diminished total protein excretion throughout this period primarily by protecting against appearance of abnormal urinary proteins that characterized the untreated diabetic state; the latter exhibited albuminuria, numerous newly detected proteins between 30,000 and 65,000 daltons, and an additional 4 to 5 proteins between 70,000 and 120,000 daltons. These findings closely resembled protein patterns exhibited by 54-week spontaneously diabetic BB rats, another model for IDDM. In the reversal study, age-matched control and streptozotocin-induced diabetic rats were maintained for four weeks, and weekly 24-hour urine analyses were performed as previously described.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldehyde Reductase; Animals; Cataract; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Electrophoresis, Polyacrylamide Gel; Humans; Imidazoles; Imidazolidines; L-Iditol 2-Dehydrogenase; Proteinuria; Rats; Rats, Inbred BB

Topics: Aldehyde Reductase; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Diet; Glomerular Filtration Rate; Imidazoles; Imidazolidines; Inositol; Male; Rats; Rats, Inbred Strains; Sugar Alcohol Dehydrogenases

Topics: Aldehyde Reductase; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Imidazoles; Imidazolidines; Inositol; Kidney Glomerulus; Rats; Sodium-Potassium-Exchanging ATPase; Sorbitol; Sugar Alcohol Dehydrogenases