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12/15-lipoxygenase inhibitors in diabetic nephropathy in the rat.

Abstract
The 12/15-lipoxygenase (12/15-LO) pathway is activated in diabetes mellitus (DM), increasing 12(S)-hydroxyeicosatetraenoic acid (12-HETE). We showed that a 12-LO inhibitor, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (CDC) inhibited 12/15-LO activity in vivo and assessed the efficacy of another 12/15-LO inhibitor, N-benzyl-N-hydroxy-5-phenylpentamidine (BHPP), to diminish urinary 12-HETE and ameliorate diabetic nephropathy (DN) over 4 months. Rats studied were control (C, n=8), DM (n=6), and rats injected with BHPP (C+BHPP, n=4) and (DM+BHPP, n=5). BHPP 3 mg/kg/day decreased urinary (U) 12-HETE/creatinine (cr) by 30-50% after one injection and after 1 week of daily injections in DM rats. U 12-HETE/cr excretion increased paradoxically in controls given BHPP. There was a highly significant relationship between U 12-HETE/cr excretion and U alb/cr (r=0.79, P<10(-5)), demonstrating that renal 12/15-LO pathway activation is associated with albuminuria. BHPP did not inhibit glomerular collagen synthesis or improve histology. More sustained 12-LO inhibition may improve albuminuria in DN.
AuthorsJun Ma, Rama Natarajan, Janine LaPage, Linda Lanting, Nancy Kim, Diana Becerra, Breyon Clemmons, Cynthia C Nast, G K Surya Prakash, Mihirbaran Mandal, Sharon G Adler
JournalProstaglandins, leukotrienes, and essential fatty acids (Prostaglandins Leukot Essent Fatty Acids) Vol. 72 Issue 1 Pg. 13-20 (Jan 2005) ISSN: 0952-3278 [Print] Scotland
PMID15589395 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Amides
  • Benzylamines
  • Caffeic Acids
  • Collagen Type IV
  • Lipoxygenase Inhibitors
  • cinnamyl-3,4-dihydroxycyanocinnamate
  • N-benzyl-N-hydroxy-5-phenylpentamide
  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
  • Creatinine
Topics
  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid (urine)
  • Albuminuria
  • Amides (pharmacology)
  • Animals
  • Benzylamines (pharmacology)
  • Caffeic Acids (pharmacology)
  • Collagen Type IV (metabolism)
  • Creatinine (urine)
  • Diabetic Nephropathies (drug therapy, enzymology)
  • Kidney Glomerulus (drug effects, pathology)
  • Lipoxygenase Inhibitors (pharmacology)
  • Male
  • Rats
  • Rats, Sprague-Dawley

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