Reversal of Proteinuria by Sorbinil, an Aldose Reductase Inhibitor in Spontaneously Diabetic (BB) Rats

Beyer‐Mears, A.; Murray, Frederick T.; Val, Margarita Del; Cruz, E.; Sciadini, M.

doi:10.1159/000138367

Cited by 22 publications

(13 citation statements)

References 28 publications

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“…Initially for 3 and 4 months, ponal restat treatment protected against the in creased excretion of a series of proteins in cluding albumin in the diabetic BB rats de spite persistent hyperglycemia and glycosuria. Likewise, our previous 4-month sorbinil study and the present 6-month study showed complete protection of urinary protein excre tion in the BB diabetic rat [3]. McCaleb et al [ 16] have also shown that 6-month treatment with the ARI.…”

Section: Discussionsupporting

confidence: 82%

“…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: 63%

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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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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 63%

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

Beyer‐Mears¹,

Murray²,

Cruz³

et al. 1992

Pharmacology

Self Cite

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“…The BB rats were fed ad libitum with Purina Rodent Chow and housed individually and in isolation from all other animals. To detect onset and progression of diabetes mellitus, the glu cose content of blood and urine was analyzed as pre viously described [6]. Diagnosis of diabetes was made when blood glucose exceeded 300 mg/dl and glycos uria was present.…”

Section: Methodsmentioning

confidence: 99%

“…Diagnosis of diabetes was made when blood glucose exceeded 300 mg/dl and glycos uria was present. Diabetic rats were maintained on PZI insulin (0.5-1 units/lOOg body weight) which was administered daily as previously described [6]. The doses were sufficient to sustain body weight and avoid hypoglycemic episodes.…”

Section: Methodsmentioning

confidence: 99%

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Proteinuria Associated with Hypertension and Diabetes mellitus

Beyer‐Mears

Val²,

Cruz³

et al. 1988

Pharmacology

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Proteinuria, a complication of both diabetes mellitus and hypertension, was compared in 2 genetically induced models: insulin-dependent diabetic BB rat (BB), and Okamoto-Aoki spontaneously hypertensive Wistar rats (SHR). Both disease states were clearly distinguished from each other and their respective age-matched controls by analysis of 24-hour urine samples for glucose, urobilinogen, bilirubin and total protein. Then individual protein components between 15,000 and 120,000 daltons were separated by molecular weight and quantitated by laser densitometric analysis. The results indicated that insulin-dependent diabetic BB rats excreted urine having elevation of glucose (100–250 mg/dl), bilirubin (0.05 ± 0.03 mg/dl) and urobilinogen (6.6 ± 3.8 Ehrlich units/dl) in contrast to all age-matched SHR and normotensive Wistar-Kyoto (WKY) and nondiabetic controls, which excreted urine having normal urobilinogen and no detectable glucose or bilirubin. Both SHR and insulin-dependent BB rats exhibited proteinuria, urinary protein excretion being increased approximately 4–5 times that of their age-matched controls. BB rats excreted 18.80 ± 2.62 mg protein/day attributed to an increase in albumin and an entire array of proteins between 30,000 and 120,000 daltons not present in controls which primarily excreted proteins below 20,000 daltons. In the SHR, proteinuria did not include an array of proteins; the increase in excreted protein (39.20 ± 16 mg/day) was primarily attributed to albumin and another protein having a higher molecular weight. The SHR urinary proteins were similar to proteins excreted by streptozocin-induced, noninsulin-dependent diabetic rats treated with the aldose reductase inhibitor sorbinil. If hypertension is associated with diabetic nephropathy, our preclinical results suggest that coadministration of sorbinil with antihypertensive therapy may promote a positive synergistic effect further diminishing proteinuria.

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Biochemical manifestations of diabetes mellitus in microscopic layers of the cornea and retina

Marano

Matschinsky

1989

Diabetes Metab. Rev.

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Reversal of Proteinuria by Sorbinil, an Aldose Reductase Inhibitor in Spontaneously Diabetic (BB) Rats

Cited by 22 publications

References 28 publications

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

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

Proteinuria Associated with Hypertension and Diabetes mellitus

Biochemical manifestations of diabetes mellitus in microscopic layers of the cornea and retina

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