Diminished Proteinuria in Diabetes mellitus by Sorbinil, an Aldose Reductase Inhibitor

Beyer‐Mears, A.; Cruz, E.; Edelist, T.; Varagiannis, E.

doi:10.1159/000138152

Cited by 65 publications

(26 citation statements)

References 10 publications

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“…Mean_+ SEM are shown. There were six rats in each group UAE/GFR GFR/kg body Bg/ml.min ~ mass ml-min-l/kg This study has confirmed that inhibition of the enzyme aldose reductase by two structurally unrelated compounds partially prevents the increase in UAE observed in rats with diabetes induced by STZ [15,17,21,22]. It has also confirmed the findings of Craven et al [22] that the enhanced PG production by glomeruli isolated from STZ diabetic rats is reduced by treatment with ARI.…”

Section: Glornerular Sorbitol Content In Non-diabetic Rats and Rats Asupporting

confidence: 67%

“…These include increased glomerular filtration rate (GFR) [1][2][3][4][5][6][7][8][9][10][11][12][13], increased urinary albumin excretion (UAE) [13][14][15][16][17], increased production of vasoactive prostaglandins (PGs) by renal glomeruli [10,[18][19][20], and increased glomerular sorbitol accumulation [21]. Although there are several plausible ways in which these changes could be related, the data linking these phenomena have been conflicting and confusing.…”

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confidence: 99%

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The effect of aldose reductase inhibitors on glomerular prostaglandin production and urinary albumin excretion in experimental diabetes mellitus

et al. 1991

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Summary. The effect of two structurally unrelated aldose reductase inhibitors, sorbinil and ponalrestat, on glomerular prostaglandin production and urinary albumin excretion was investigated in rats with diabetes induced by streptozotocin. it was found that both aldose reductase inhibitors, when administered from the time of induction of the diabetes, significantly decreased the raised urinary albumin excretion in the diabetic rats, although it remained elevated compared with non-diabetic rats. Glomerular prostaglandin E and 6-ketoprostaglandin F,c~ production was significantly increased in glomeruli obtained from the diabetic rats. Inhibition of aldose reductase caused a reduction in the raised glomerular prostaglandin production, although this remained above that observed in the non-diabetic rats. Subsequent experiments were performed to determine whether the effects of the aldose reductase inhibitors could be explained by effects on glomerular filtration rate. It was found that ponalrestat, at a dose which markedly reduced urinary albumin excretion, did not significantly affect glomerular filtration rate in nondiabetic rats, rats with untreated streptozotocin-induced diabetes and rats with diabetes partially treated with low dose insulin. Glomerular sorbitol concentrations were significantly elevated in untreated diabetic rats as early as two weeks after the induction of diabetes. It is concluded that the administration of aldose reductase inhibitors from the time of induction of diabetes significantly reduces glomerular prostaglandin production and urinary albumin excretion. The latter effect is not due to an effect on glomerular filtration rate. Increased polyol pathway activity may account in part for the increased glomerular prostaglandin production and urinary albumin excretion in early experimental diabetes.Key words: Diabetic nephropathy, albuminuria, aldose reductase inhibitors, prostaglandins.A number of functional and biochemical changes have been demonstrated in early diabetes in humans and in experimental animals which have been postulated to lead to the later development of the structural changes that characterise diabetic nephropathy. These include increased glomerular filtration rate (GFR) [1-13], increased urinary albumin excretion (UAE) [13][14][15][16][17], increased production of vasoactive prostaglandins (PGs) by renal glomeruli [10,[18][19][20], and increased glomerular sorbitol accumulation [21]. Although there are several plausible ways in which these changes could be related, the data linking these phenomena have been conflicting and confusing. For example, studies using aldose reductase inhibitors (ARI) to inhibit sorbitol accumulation have been reported to prevent the increased GFR and reduce the albuminuria seen in rats with diabetes induced by streptozotocin (STZ) [17], or to have no effect on either parameter [16], or to reduce the raised GFR but by effects apparently independent of reduction in sorbitol levels [22]. Moreover, the role of elevated PG production in the hyperfiltrat...

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Section: Glornerular Sorbitol Content In Non-diabetic Rats and Rats Asupporting

confidence: 67%

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confidence: 99%

The effect of aldose reductase inhibitors on glomerular prostaglandin production and urinary albumin excretion in experimental diabetes mellitus

et al. 1991

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“…Previously, we reported that the aldose reductase inhibi tor (ARI), sorbinil, prevented and/or reversed proteinuria as determined by analysis of total urinary' protein excretion and the array of individual urinary proteins for a period of 4 months [3][4][5], In the present study, the objec tives were 2-fold. First, the sorbinil study was extended to 6 months.…”

Section: Introductionmentioning

confidence: 62%

Comparison of Sorbinil and Ponalrestat (Statil) Diminution of Proteinuria in the BB Rat

Beyer‐Mears¹,

Murray²,

Cruz³

et al. 1992

Pharmacology

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Diabetic nephropathy leading to kidney failure is a major complication of type I (insulin-dependent) diabetes mellitus and is associated with progressive proteinuria. In the present 6-month study, effects of two structurally dissimilar aldose reductase inhibitors (sorbinil and ponalrestat or Statil) were examined on prevention of proteinuria in insulin-dependent spontaneously diabetic BB rats and compared with age-matched BB resistant controls. Prior to aldose reductase inhibitor treatment, all diabetic BB rats exhibited hyperglycemia (>300 mg/dl), glycosuria (>2,000 mg/dl) and 24-hour urinary protein excretion ranging from 5.01 to 11.23 mg/day. After daily administration of ponalrestat (20 mg/kg) for 3 months, 24-hour urinary protein excretion was 11.53 ± 1.76 mg/day in ponalrestat-treated rats, despite persistence of hyperglycemia (444 ± 31 mg/dl) and glycosuria (>2,000 mg/dl); by contrast, urinary protein excretion was 17.76 ± 2.59 mg/day in the control group of untreated BB diabetic rats. Ponalrestat initially protected against excretion of an array of urinary proteins having molecular weights between 30,000 and 100,000 daltons. These effects sustained throughout the 4th month of treatment, tended to change toward valves in control rats by the 5th month. At the end of 6 months, ponalrestat-treated diabetic rats excreted 18.73 ± 3.20 mg/day of protein, similar to valves in untreated BB diabetic rats; both demonstrated a 4-fold increase in urinary protein excretion when compared to age-matched BB resistant controls. Proteinuria was attributed to an increase in albumin and an array of proteins having molecular weights between 30,000 and 100,000 daltons. In comparison, daily administration of sorbinil (20 mg/kg for 6 months) protected against proteinuria because daily total protein excretion (6.61 ± 2.26 mg) was not statistically significant from that of the control BB resistant rats. These results indicate that proteinuria was diminished by both aldose reductase inhibitors but with increased duration of diabetes sorbinil had a greater therapeutic effect than ponalrestat.

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“…This is deducted from short-term studies in streptozotocin diabetic (SZT-D) (IDDM) animals showing that early administration of aldose reductase inhibitors reduces the increased GFR [5,6] and partly reduces the increased urinary albumin excretion [6][7][8]24]. The results of the studies on the effect of dietary myo -inositol sUpplementation on the GFR differ.…”

Section: Discussionmentioning

confidence: 99%

Effect of myo-inositol supplementation on the development of renal pathological changes in the Cohen diabetic (type 2) rat

Cohen

Wald²,

Popovtzer³

et al. 1995

Diabetologia

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Summary A lower concentration of intracellular myo-inositol has been implicated in the development of diabetic nephropathy. This was based on short-term studies showing that early administration of aldose reductase inhibitors or myo-inositol supplementation reduces increased glomerular filtration rate and partly reduces increased urinary albumin excretion in streptozotocin diabetic rats. We studied the effect of long-term (4 months) administration of 1% myo-inositol supplement to the Cohen diabetic (type 2) rat on the development of nephropathy and renal Na+-K+-ATPase. This treatment reduced the increased renal Na+-K+-ATPase activity but had no effect on blood glucose levels, body weight, increased kidney weight, or creatinine clearance and did not prevent or reduce the development of renal glomerular pathology. There was no correlation between the level of Na+-K § ATPase activity and the degree of nephropathy. It is possible that the renal pathological changes are due to metabolic and humoral factors resulting from hyperglycaemia, other than myo-inositol depletion. The fact that rnyo-inositol treatment had no effect on the development of renal pathological changes but was shown to have a beneficial effect on restoring impaired conduction velocity and on the disruption of structural elements in the nerve indicates that the effect of the biological changes ensuing from hyperglycaemia vary in different tissues depending on local conditions. [Diabetologia (1995) 38: 899-905] Key words Non-insulin-dependent diabetes mellitus (type 2), myo-inositol, glomerulosclerosis, Na+-K +-ATPase, Cohen-diabetic rat.It has been suggested that polyol pathway hyperactivity contributes to the pathogenesis of diabetic renal complications [1][2][3][4]. This was based on the observation that treatment with aldose reductase inhibitors and myo-inositol supplements reduces the increased glomerular filtration rate [5,6] Abbreviations: Pi, Inorganic phosphate; IDDM, insulin-dependent diabetes mellitus; NIDDM, non-insulin-dependent diabetes mellitus; STZ-D, streptozotocin diabetic rats; GS, glomerulosclerosis; PG, prostaglandin.creased urinary albumin excretion [6][7][8] in diabetic animals.Most of these observations have been made in short-term type i streptozotocin diabetic rats (SZT-D). The purpose of the present study was to evaluate the effect of long-term supplementation of myo-inositol in the Cohen diabetic rat (type 2) on the development of pathological changes and Na+-K+-ATPase activity in the kidneys. Materials and methodsAnimals. The Cohen diabetic rat shares essential features with human non-insulin-dependent diabetes such as genetic and environmental disposition [9], an early phase of hyperinsulinaemia, and insulin resistance, followed by hypoinsulinaemia [10], a decreased number and sensitivity of insulin receptors

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Diminished Proteinuria in Diabetes mellitus by Sorbinil, an Aldose Reductase Inhibitor

Cited by 65 publications

References 10 publications

The effect of aldose reductase inhibitors on glomerular prostaglandin production and urinary albumin excretion in experimental diabetes mellitus

The effect of aldose reductase inhibitors on glomerular prostaglandin production and urinary albumin excretion in experimental diabetes mellitus

Comparison of Sorbinil and Ponalrestat (Statil) Diminution of Proteinuria in the BB Rat

Effect of myo-inositol supplementation on the development of renal pathological changes in the Cohen diabetic (type 2) rat

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