title: Response of capillary cell death to aminoguanidine predicts the development of retinopathy: comparison of diabetes and galactosemia.
abstract: OBJECTIVE
  To examine the relationship between early retinal capillary cell apoptosis and late histologic lesions of diabetic retinopathy and to compare the effects of aminoguanidine (AMG) on the retinopathies caused by diabetes and galactose feeding.
  
  
  METHODS
  Rats with alloxan-induced diabetes and rats fed a 30% galactose diet (known to induce diabetic-like retinopathy) were assigned randomly to receive diet with (2.5 g/kg diet) or without AMG. After 6 to 8 months of diabetes or galactosemia, retinal trypsin digests were prepared, and capillary cell apoptosis was quantitated using the Tdt-mediated dUTP nick-end labeling (TUNEL) reaction in association with morphologic evidence of nuclear fragmentation. At 18 months duration, pericyte ghosts and acellular capillaries were quantitated in the isolated vasculature. Several advanced glycation end products (AGEs) were measured at 4 months of study and at 18 months of study by established methods to assess biochemical effects of AMG.
  
  
  RESULTS
  As expected, both diabetic and galactosemic rats showed increased frequency of TUNEL-positive capillary cells at 6 to 8 months and vascular lesions characteristic of retinopathy at 18 months. AMG inhibited both the early apoptosis and late histopathology in the diabetic rats, but neither of these abnormalities in the galactosemic rats. In contrast to its preventative effect on retinopathy in the diabetic rats, AMG showed no inhibitory effect on levels of hemoglobin AGE, or tail collagen pentosidine, fluorescence, and thermal breaking time. Diabetes of 4 months' duration did not cause a detectable increase in retinal levels of several AGEs.
  
  
  CONCLUSIONS
  The frequency of early apoptosis in retinal microvascular cells predicted the development of the histologic lesions of retinopathy in diabetes as well as in galactosemia. The beneficial effect of AMG on retinal lesions in diabetes is exerted on pathways that are either not operative or are less important in galactosemia and that may not relate to the accumulation of AGEs.
authors.affiliation: Departments of Medicine, Ophthalmology, Pharmacology and Center for Diabetes Research, Case Western Reserve University, Cleveland, Ohio, USA. tsk@po.cwru.edu
authors.forename: T S
authors.initials: TS
authors.lastname: Kern
authors.forename: J
authors.initials: J
authors.lastname: Tang
authors.forename: M
authors.initials: M
authors.lastname: Mizutani
authors.forename: R A
authors.initials: RA
authors.lastname: Kowluru
authors.forename: R H
authors.initials: RH
authors.lastname: Nagaraj
authors.forename: G
authors.initials: G
authors.lastname: Romeo
authors.forename: F
authors.initials: F
authors.lastname: Podesta
authors.forename: M
authors.initials: M
authors.lastname: Lorenzi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002196:Capillaries / Q000166:cytology; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D004730:Endothelium, Vascular / Q000187:drug effects*; D005690:Galactose / Q000008:administration & dosage; D005693:Galactosemias / Q000150:complications* / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D008297:Male; D020286:Pericytes / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012171:Retinal Vessels / Q000187:drug effects* / Q000378:metabolism
chemical_list: D017127:Glycation End Products, Advanced; D006146:Guanidines; C004479:pimagedine; D005690:Galactose