rhodanine and Diabetic-Nephropathies

Diabetic neuropathy (DN) is the most frequent among peripheral neuropathies. Since its pathophysiology is so complicated, neither classification nor therapeutic management of DN has been established. Sensory/autonomic polyneuropathy (DP) is the main type of DN. Since diabetic patients occasionally have one or more subtypes of DN and/or other polyneuropathy including treatable neuropathy like CIDP, the treatment for DP has to be conducted after excluding the possibility of other conditions. Glycemic control is most essential to prevent the development of DP. However, it is practically difficult to keep HbA1c under 6.5% so that drinking and smoking better be restricted and blood pressure be properly maintained to retard the progression of DP. Aldose reductase inhibitor is only one commercially available drug for DP and its efficacy must be evaluated by nerve function tests along with subjective symptoms. More vigorous therapeutic procedure is expected by obtaining not only more potential drugs based on pathogenic mechanisms but also the technique targeting of DNA/siRNA of given peptides at dorsal root ganglion neurons.

Topics: Aldehyde Reductase; Diabetic Nephropathies; Enzyme Inhibitors; Genetic Therapy; Humans; Hypoglycemic Agents; Imidazolidines; Neuralgia; Neurologic Examination; Regenerative Medicine; Rhodanine; Thiazolidines

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

Epalrestat is an inhibitor of aldose reductase in the polyol pathway and is used for the management of diabetic neuropathy clinically. Our pilot experiments and accumulated evidences showed that epalrestat inhibited polyol pathway and reduced sorbitol production, and suggested the potential renal protection effects of epalrestat on diabetic nephropathy (DN). To evaluate the protective effect of epalrestat, the db/db mice were used and exposed to epalrestat for 8 weeks, both the physiopathological condition and function of kidney were examined. For the first time, we showed that epalrestat markedly reduced albuminuria and alleviated the podocyte foot process fusion and interstitial fibrosis of db/db mice. Metabolomics was employed, and metabolites in the plasma, renal cortex, and urine were profiled using a gas chromatography-mass spectrometry (GC/MS)-based metabolomic platform. We observed an elevation of sorbitol and fructose, and a decrease of myo-inositol in the renal cortex of db/db mice. Epalrestat reversed the renal accumulation of the polyol pathway metabolites of sorbitol and fructose, and increased myo-inositol level. Moreover, the upregulation of aldose reductase, fibronectin, collagen III, and TGF-β1 in renal cortex of db/db mice was downregulated by epalrestat. The data suggested that epalrestat has protective effects on DN, and the inhibition of aldose reductase and the modulation of polyol pathway in nephritic cells be a potentially therapeutic strategy for DN.

Topics: Albuminuria; Aldehyde Reductase; Animals; Diabetic Nephropathies; Enzyme Inhibitors; Fructose; Inositol; Kidney; Male; Metabolomics; Mice; Protective Agents; Rhodanine; Sorbitol; Thiazolidines

An accelerated polyol pathway in diabetes contributes to the development of diabetic complications. To elucidate diabetic nephropathy involving also renal tubular damage, we measured urinary sorbitol concentration concomitantly with urinary N-acetyl-D-glucosaminidase (NAG) excretion in WBN-kob diabetic rats.Twenty-four-hour urinary sorbitol concentrations increased in the diabetic rats in parallel with whole blood sorbitol concentrations. An increase in 24-h urinary NAG excretion coincided with the elevated urinary sorbitol levels in the diabetic rats. The administration of epalrestat, an aldose reductase inhibitor, reduced the increased whole blood and urinary sorbitol concentrations and urinary NAG excretion concomitantly with renal aldose reductase inhibition in the diabetic rats. These results indicate that diabetic nephropathy involves distorted cell function of renal tubules, and that treatment with epalrestat may prevent at least the progress of the nephropathy.

Topics: Acetylglucosaminidase; Aldehyde Reductase; Animals; Diabetic Nephropathies; Kidney; Male; Models, Animal; Rats; Rats, Wistar; Rhodanine; Sorbitol; Thiazolidines

Topics: Adolescent; Adult; Aged; Aldehyde Reductase; Blood Glucose; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Enzyme Inhibitors; Erythrocytes; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Regression Analysis; Reproducibility of Results; Rhodanine; Sorbitol; Spectrophotometry; Thiazolidines

The present study was conducted in order to determine whether an aldose reductase inhibitor (ARI), epalrestat, prevents the progression of diabetic nephropathy in rats. Rats were made diabetic by intravenous injection of streptozotocin (STZ 50 mg/kg) and epalrestat (100 mg/kg) was administered orally through a gastric tube once daily for 4 weeks. Examination by electron microscope revealed that the number of anionic sites (AS) in the lamina rara externa per 1000 nm of glomerular basement membrane (GBM) was significantly decreased in diabetic rats compared to control values (17.6 + or - 0.4 vs. 21.9 + or -0.4, P < 0.01), whereas, significant recovery (20.3 + or - 0.7, P < 0.05) was observed after 4 weeks of epalrestat treatment. Urinary albumin excretion (UAE) rate was markedly increased in diabetic rats and the treatment resulted in its significant suppression from diabetic rats. In conclusion, administration of epalrestat to diabetic rats is capable of preventing a reduction in the number of AS in GBM which would ameliorate an increased permeability of the basement membrane leading to albuminuria.

Topics: Administration, Oral; Albuminuria; Aldehyde Reductase; Animals; Anions; Basement Membrane; Blood Glucose; Blood Pressure; Cohort Studies; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme Inhibitors; Erythrocytes; Kidney Glomerulus; Male; Rats; Rats, Wistar; Rhodanine; Sorbitol; Thiazolidines; Time Factors

In order to clarify the possible contribution of the abnormal polyol pathway to the development of diabetic nephropathy, the effect of aldose reductase inhibitor on renal function and morphology was examined in streptozotocin (STZ)-induced diabetic rats. Six months after STZ injection, glomerular filtration rate and renal plasma flow showed marked decline with significant increase in nuclear-free mesangial area (MA) and relative mesangial area (RMA; MA per glomerular area) in diabetic rats. Oral administration of an aldose reductase inhibitor, Epalrestat, prevented renal hypofunction and mesangial expansion in diabetic rats without influencing the levels of blood glucose. These results suggest that the abnormal polyol pathway in diabetic rats is closely related to the development of mesangial expansion, a morphologic representative of diabetic glomerulopathy, and renal hypofunction.

Topics: Albuminuria; Aldehyde Reductase; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme-Linked Immunosorbent Assay; Glomerular Filtration Rate; Glomerular Mesangium; Kidney; Male; Organ Size; Rats; Rats, Sprague-Dawley; Renal Circulation; Rhodanine; Thiazolidines

Topics: Aldehyde Reductase; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetic Nephropathies; Diabetic Neuropathies; Glycosylation; Humans; Inositol; Proteins; Rhodanine; Sorbitol; Thiazolidines