12/15-Lipoxygenase inhibitors in diabetic nephropathy in the rat

被引：31

作者：

Ma, J ^{[1
]}

Natarajan, R ^{[1
]}

LaPage, J ^{[1
]}

Lanting, L ^{[1
]}

Kim, N ^{[1
]}

Becerra, D ^{[1
]}

Clemmons, B ^{[1
]}

Nast, CC ^{[1
]}

Prakash, GKS ^{[1
]}

Mandal, M ^{[1
]}

Adler, SG ^{[1
]}

机构：

[1] Univ Calif Los Angeles, Div Nephrol, Res & Educ Inst, Torrance, CA 90502 USA

来源：

PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS | 2005年 / 72卷 / 01期

关键词：

D O I：

10.1016/j.plefa.2004.06.004

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 I 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. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：13 / 20

页数：8

共 39 条

[1]

Abboud HE, 1997, KIDNEY INT, pS3

[2] A 12-lipoxygenase product, 12-hydroxyeicosatetraenoic acid, is increased in diabetics with incipient and early renal disease [J].

Antonipillai, I ;

Nadler, J ;

Vu, EJ ;

Bughi, S ;

Natarajan, R ;

Horton, R .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1996, 81 (05) :1940-1945

[3]

ARDAILLOU R, 1989, ADV EXP MED BIOL, V259, P49

[4] Glucose-induced oxidative stress in mesangial cells [J].

Catherwood, MA ;

Powell, LA ;

Anderson, P ;

McMaster, D ;

Sharpe, PC ;

Trimble, ER .

KIDNEY INTERNATIONAL, 2002, 61 (02) :599-608

[5]

CHEN XS, 1994, J BIOL CHEM, V269, P13979

[6] NOVEL CAFFEIC ACID-DERIVATIVES - EXTREMELY POTENT INHIBITORS OF 12-LIPOXYGENASE [J].

CHO, H ;

UEDA, M ;

TAMAOKA, M ;

HAMAGUCHI, M ;

AISAKA, K ;

KISO, Y ;

INOUE, T ;

OGINO, R ;

TATSUOKA, T ;

ISHIHARA, T ;

NOGUCHI, T ;

MORITA, I ;

MUROTA, S .

JOURNAL OF MEDICINAL CHEMISTRY, 1991, 34 (04) :1503-1505

[7] Lipoxygenase-dependent mechanisms in hypertension [J].

DelliPizzi, A ;

Guan, H ;

Tong, XG ;

Takizawa, H ;

Nasjletti, A .

CLINICAL AND EXPERIMENTAL HYPERTENSION, 2000, 22 (02) :181-192

[8] The molecular biology of mammalian lipoxygenases and the quest for eicosanoid functions using lipoxygenase-deficient mice [J].

Funk, CD .

BIOCHIMICA ET BIOPHYSICA ACTA-LIPIDS AND LIPID METABOLISM, 1996, 1304 (01) :65-84

[9] EVIDENCE THAT A LEUKOCYTE TYPE OF 12-LIPOXYGENASE IS EXPRESSED AND REGULATED BY ANGIOTENSIN-II IN HUMAN ADRENAL GLOMERULOSA CELLS [J].

GU, JL ;

NATARAJAN, R ;

BENEZRA, J ;

VALENTE, G ;

SCOTT, S ;

YOSHIMOTO, T ;

YAMAMOTO, S ;

ROSSI, JJ ;

NADLER, JL .

ENDOCRINOLOGY, 1994, 134 (01) :70-77

[10] Ribozyme-mediated inhibition of rat leukocyte-type 12-lipoxygenase prevents intimal hyperplasia in balloon-injured rat carotid arteries [J].

Gu, JL ;

Pei, H ;

Thomas, L ;

Nadler, JL ;

Rossi, JJ ;

Lanting, L ;

Natarajan, R .

CIRCULATION, 2001, 103 (10) :1446-1452

← 1 2 3 4 →