Comparison of sorbinil and ponalrestat (Statil) diminution of proteinuria in the BB rat.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Beyer-Mears
A
A
Department of Physiology, UMDNJ-New Jersey Medical, Newark 07103.
Murray
F T
FT
Cruz
E
E
Rountree
J
J
Sciadini
M
M
D000284:Administration, Oral; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000652:urine; D007093:Imidazoles / Q000627:therapeutic use*; D048289:Imidazolidines; D008297:Male; D010793:Phthalazines / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy*; D051381:Rats; D011913:Rats, Inbred BB
D001786:Blood Glucose; D007093:Imidazoles; D048289:Imidazolidines; D010793:Phthalazines; C042829:ponalrestat; D000449:Aldehyde Reductase; C026411:sorbinil