title: A flavonoid fraction purified from Rutaceae aurantiae (Daflon(R)) inhibiting AGE formation, reduces urinary albumin clearance and corrects hypoalbuminemia in normotensive and hypertensive diabetic rats.
abstract: OBJECTIVE
  Advanced glycation endproducts (AGEs) have been shown to contribute to alteration of glomerular permselectivity to proteins in diabetes. Oxidative stress is required for AGE formation. Therefore we studied the effect of an antioxidant micronized purified flavonoid fraction (MPFF, Daflon(R) 500 mg), on urinary albumin clearance in diabetic rats.
  
  
  METHODS
  Hyperglycaemia was induced by streptozotocin 55 mg/kg IM at days 0 and 7 in normotensive Wistar rats (NWR, diabetes duration 5 months) or hypertensive Wistar Kyoto rats (SHR, diabetes duration 2 months). MPFF was administered at 300 mg/kg/day, from day -2 until sacrifice.
  
  
  RESULTS
  After 5 months of diabetes in NWR, MPFF reduced albumin clearance from 729±92 to 392±60 nl/min/kg, p<0.01, and restored albuminemia from 20.4±0.9 to 24.0±1 g/l, p<0.05; albumin fractional clearance was significantly diminished in the flavonoid-treated diabetic rats (0.360±0.037‰ versus 1.335±0.430‰ in the diabetic controls, p<0.001); MPFF did not significantly modify blood glucose and plasma fructosamine levels. After 2 months of diabetes in SHR, MPFF reduced albumin clearance from 243±121 to 101±47 nl/min/kg, p<0.05, and restored albuminemia from 21.1±1.6 to 26.7±2.2 g/l (p<0.05); MPFF also decreased plasma fluorescence characteristic of AGEs (p<0.02). Besides hesperetin, a main metabolite of MPFF recovered in plasma, inhibited in vitro the formation of the crosslinking AGE pentosidine in collagen incubated with high glucose (p<0.001).
  
  
  CONCLUSIONS
  Our results confirm the role of glycoxidative stress in diabetic nephropathy. MPFF might be useful as complementary treatment for preventing diabetic microangiopathy.
authors: Equipe de Recherche sur la Biochimie et la Pharmacologie des Vaisseaux et du Rein", Laboratoire de Pharmacologie, Faculté de Pharmacie, Université de Paris V & VI, France; Laboratoire de Biochimie, Hôpital Bichat, Paris, France.
authors: P
authors: P
authors: Urios
authors: Equipe de Recherche sur la Biochimie et la Pharmacologie des Vaisseaux et du Rein", Laboratoire de Pharmacologie, Faculté de Pharmacie, Université de Paris V & VI, France.
authors: I
authors: I
authors: Kassab
authors: Equipe de Recherche sur la Biochimie et la Pharmacologie des Vaisseaux et du Rein", Laboratoire de Pharmacologie, Faculté de Pharmacie, Université de Paris V & VI, France; Laboratoire de Biochimie, Hôpital Ambroise-Paré, Boulogne, France.
authors: A M
authors: AM
authors: Grigorova-Borsos
authors: Equipe de Recherche sur la Biochimie et la Pharmacologie des Vaisseaux et du Rein", Laboratoire de Pharmacologie, Faculté de Pharmacie, Université de Paris V & VI, France.
authors: R
authors: R
authors: Guillot
authors: Institut Polytechnique LaSalle-Beauvais, Unité de recherche EGEAL, Beauvais, France.
authors: P
authors: P
authors: Jacolot
authors: Institut Polytechnique LaSalle-Beauvais, Unité de recherche EGEAL, Beauvais, France.
authors: F
authors: F
authors: Tessier
authors: Equipe de Recherche sur la Biochimie et la Pharmacologie des Vaisseaux et du Rein", Laboratoire de Pharmacologie, Faculté de Pharmacie, Université de Paris V & VI, France.
authors: J
authors: J
authors: Peyroux
authors: Equipe de Recherche sur la Biochimie et la Pharmacologie des Vaisseaux et du Rein", Laboratoire de Pharmacologie, Faculté de Pharmacie, Université de Paris V & VI, France; Laboratoire d'Hormonologie, Hôpital Saint-Vincent-de-Paul, Paris, France. Electronic address: michel.sternberg@wanadoo.fr.
authors: M
authors: M
authors: Sternberg
mesh_terms: D000419:Albuminuria / Q000188:drug therapy*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000517:prevention & control; D004145:Diosmin / Q000627:therapeutic use*; D005419:Flavonoids / Q000627:therapeutic use; D019270:Fructosamine / Q000097:blood; D050533:Glomerular Basement Membrane / Q000187:drug effects / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000032:analysis / Q000378:metabolism*; D006569:Hesperidin / Q000627:therapeutic use; D006943:Hyperglycemia / Q000139:chemically induced / Q000188:drug therapy; D034141:Hypoalbuminemia / Q000188:drug therapy*; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D008517:Phytotherapy; D010936:Plant Extracts; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D027821:Rutaceae / Q000737:chemistry*
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D005419:Flavonoids; D017127:Glycation End Products, Advanced; D010936:Plant Extracts; D019270:Fructosamine; D004145:Diosmin; D006569:Hesperidin; C013015:hesperetin
keywords: Advanced glycation endproducts; Albuminuria; Experimental diabetic nephropathy; Flavonoids; Spontaneously hypertensive rats