title: Prevention of early glomerulopathy with tolrestat in the streptozotocin-induced diabetic rat.
abstract: Hyperglycemia is of central importance in the pathogenesis of the complications of diabetes mellitus. Glucose activation of the polyol pathway may lead to renal arteriolar smooth muscle and glomerular mesangial cell hypocontractility. In the streptozotocin-induced diabetic rat, the effect of the aldose reductase inhibitor, tolrestat, in preventing glomerular hyperfiltration, renal hypertrophy, extracellular matrix accumulation, and mesangial cell hypocontractility was addressed. Streptozotocin-induced diabetic rats were followed for 12 weeks and half received tolrestat (25 mg/kg per day). Increased glomerular filtration rate was prevented by tolrestat (3.1 +/- 0.3 vs. 1.8 +/- 0.2 mL/min, diabetes vs. diabetes + tolrestat, p < 0.01), in part by reduction of the filtration fraction (0.39 +/- 0.03 vs. 0.29 +/- 0.01, diabetes vs. diabetes + tolrestat, p < 0.01). Tolrestat prevented the raised albumin excretion rates (3594 +/- 1154 vs. 713 +/- 161 mg/24 h, diabetes vs. diabetes + tolrestat, p < 0.01). Endothelin-1-induced contraction of isolated glomeruli was normal in tolrestat-treated diabetic animals compared with the hypocontractile diabetic glomeruli. Tolrestat prevented glomerular hypertrophy (1.86 +/- 0.10 vs. 1.49 +/- 0.03 microns 2 x 10(5), diabetes vs. diabetes + tolrestat, p < 0.001) and attenuated the accumulation of basement-membrane-like material (50.2 +/- 0.4% vs. 46.4 +/- 0.8%, diabetes vs. diabetes+tolrestat, p < 0.001). Fractional mesangial expansion was unchanged in tolrestat-treated diabetic rats compared with untreated animals. Tolrestat prevents the functional changes of glomerular hyperfiltration, mesangial cell hypocontractility, and increased glomerular permeability to albumin. Polyol accumulation may have differential effects on glomerular growth and extracellular matrix accumulation in early diabetic nephropathy.
authors.affiliation: Department of Medicine, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: S M
authors.initials: SM
authors.lastname: Donnelly
authors.forename: X P
authors.initials: XP
authors.lastname: Zhou
authors.forename: J T
authors.initials: JT
authors.lastname: Huang
authors.forename: C I
authors.initials: CI
authors.lastname: Whiteside
mesh_terms: D000665:Ampholyte Mixtures / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology*; D008297:Male; D009281:Naphthalenes / Q000627:therapeutic use*; D011108:Polymers / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000378:metabolism
chemical_list: D000665:Ampholyte Mixtures; D009281:Naphthalenes; D011108:Polymers; C024617:polyol; C040550:tolrestat