12/15-lipoxygenase inhibitors in diabetic nephropathy in the rat.
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.
Ma
Jun
J
Division of Nephrology, Harbor-UCLA Research and Education Institute, 1124 W Carson Street, Torrance, CA 90502, USA.
Natarajan
Rama
R
LaPage
Janine
J
Lanting
Linda
L
Kim
Nancy
N
Becerra
Diana
D
Clemmons
Breyon
B
Nast
Cynthia C
CC
Surya Prakash
G K
GK
Mandal
Mihirbaran
M
Adler
Sharon G
SG
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000652:urine; D000419:Albuminuria; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D002109:Caffeic Acids / Q000494:pharmacology*; D024141:Collagen Type IV / Q000378:metabolism; D003404:Creatinine / Q000652:urine; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000201:enzymology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D000577:Amides; D001596:Benzylamines; D002109:Caffeic Acids; D024141:Collagen Type IV; D016859:Lipoxygenase Inhibitors; C099255:cinnamyl-3,4-dihydroxycyanocinnamate; C085219:N-benzyl-N-hydroxy-5-phenylpentamide; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D003404:Creatinine