Sorbinil does not prevent hyperfiltration, elevated ultrafiltration pressure and albuminuria in streptozotocin-diabetic rats

Abstract

Summary. The effects of aldose reductase inhibition on kidney function were studied in rats with streptozotocin-induced diabetes mellitus. Diabetic rats were fed sorbinil (20 and 50 mg/kg) by daily gastric garage and were compared with untreated diabetic rats and normal rats. The rats were under daily supervision with regard to blood glucose control, insulin administration and body weight. The aim was to promote continuous body growth and to maintain the blood glucose concentration at around 22 mmol/1 without large day-today fluctuations. The renal functional changes observed in this well-established diabetic model closely resembled those reported in human Type 1 (insulin-dependent) diabetes mellitus. Sorbinil treatment completely prevented renal cortical sorbitot accumulation, but did not abolish kidney enlargement or the increase in ultrafiltration pressure and glomerular filtration rate. Albumin excretion was increased to the same extent in the sorbinil-treated and in the untreated diabetic rats. We conclude that increased metabolism of glucose to sorbitol does not cause the hyperfiltration in rats with streptozotocin-induced diabetes.Key words: Streptozotocin diabetic rat, aldose reductase inhibition, glomerular filtration rate, ultrafiltration pressure, albuminuria.Glomerular hyperfiltration, intrarenal hypertension and kidney enlargement are typical findings in the early stage of human Type 1 (insulin-dependent) diabetes mellitus as well as in experimental diabetes [1][2][3][4]. It has been shown that in experimental diabetes, elevations in single nephron glomerular filtration rate (SNGFR) result from concomitant elevations in ultrafiltration pressure and glomerular plasma flow [5]. It has been suggested that these early glomerular haemodynamic abnormalities, and in particular the elevated ultrafiltration pressure, constitute the major pathogenetic factor in the progressive glomerular sclerosis that eventually develops in a substantial number of Type 1 diabetic patients [6].The mechanisms behind intrarenal hypertension and glomerular hyperfiltration in diabetes have not been fully clarified. One hypothesis suggests that disturbances in the polyol pathway induced by the increased cellular uptake of glucose via an insulin-independent transport system wilI alter the regulation of renal haemodynamics [7]. Evidence has been presented which both supports and rejects this hypothesis. Variations in the severity of diabetes and variations in diabetic control may have contributed to the inconsistencies in the results [5].Such inconsistencies in previous reports indicate the need for a study with a well-standardized experimental protocol. This need is emphasized by the fact that numerous clinical studies have recently been started to test the effects of aldose reductase inhibitors on the various complications of diabetes in humans. The present study performed on rats with streptozotocin-induced diabetes has attempted to meet the above-mentioned need. The protocols were rigorously standardized so that the rats would p...

Redox state-dependent and sorbitol accumulation-independent diabetic albuminuria in mice with transgene-derived human aldose reductase and sorbitol dehydrogenase deficiency

“…Excessive accumulation of polyol has been postulated as a factor for diabetic nephropathy. Animal studies in rats have been conducted on the role of polyol pathway for the development of diabetic nephropathy [6,8,9,10]. In this study, we created four different genetically modified mice to attain the maximum accumulation of renal sorbitol by cross-breeding hAR-Tg and SDH-deficient mice.…”

“…Some investigators have reported that AR inhibitor has a beneficial effect on the development of albuminuria [6,7,8], whereas others found no beneficial effects [9,10,11]. The polyol pathway converts glucose to sorbitol by NADPH-dependent AR (E.C.…”

Rapid development of glomerulosclerosis in diabetic Dahl salt-sensitive rats

“…After 60 min equilibration time urine was collected from tubes placed in both ureters and sampled for two (45-60 min) periods [15]. Tubular sodium reabsorption was calculated from the filtered and excreted sodium measured during the clearance study.…”

Mesangial Cell Dysfunction as a Pathogenesis of Diabetic Nephropathy

“…Mesangial expansion was also ameliorated by the aldose reductase inhibitor in diabetic rats [34,35]. However, other reports have not been able to confirm the effect of the aldose reductase inhibitor on albuminuria, hyperfiltration, or mesangial expansion in diabetic animals [36,37].…”