Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney

被引:448
作者
Gorin, Y
Block, K
Hernandez, J
Bhandari, B
Wagner, B
Barnes, JL
Abboud, HE
机构
[1] Univ Texas, Hlth Sci Ctr, Dept Med, Div Nephrol, San Antonio, TX 78229 USA
[2] S Texas Vet Hlth Care Syst, Audie L Murphy Mem Hosp Div, San Antonio, TX 78229 USA
关键词
D O I
10.1074/jbc.M502412200
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
Renal hypertrophy and extracellular matrix accumulation are early features of diabetic nephropathy. We investigated the role of the NAD(P) H oxidase Nox4 in generation of reactive oxygen species (ROS), hypertrophy, and fibronectin expression in a rat model of type 1 diabetes induced by streptozotocin. Phosphorothioated antisense (AS) or sense oligonucleotides for Nox4 were administered for 2 weeks with an osmotic minipump 72 h after streptozotocin treatment. Nox4 protein expression was increased in diabetic kidney cortex compared with non-diabetic controls and was down-regulated in AS-treated animals. AS oligonucleotides inhibited NADPH-dependent ROS generation in renal cortical and glomerular homogenates. ROS generation by intact isolated glomeruli from diabetic animals was increased compared with glomeruli isolated from AS-treated animals. AS treatment reduced whole kidney and glomerular hypertrophy. Moreover, the increased expression of fibronectin protein was markedly reduced in renal cortex including glomeruli of AS-treated diabetic rats. Akt/protein kinase B and ERK1/2, two protein kinases critical for cell growth and hypertrophy, were activated in diabetes, and AS treatment almost abolished their activation. In cultured mesangial cells, high glucose increased NADPH oxidase activity and fibronectin expression, effects that were prevented in cells transfected with AS oligonucleotides. These data establish a role for Nox4 as the major source of ROS in the kidneys during early stages of diabetes and establish that Nox4-derived ROS mediate renal hypertrophy and increased fibronectin expression.
引用
收藏
页码:39616 / 39626
页数:11
相关论文
共 62 条
[1]   DYNAMICS OF RENAL HISTAMINE IN NORMAL RAT-KIDNEY AND IN NEPHROSIS INDUCED BY AMINONUCLEOSIDE OF PUROMYCIN [J].
ABBOUD, HE ;
OU, SL ;
VELOSA, JA ;
SHAH, SV ;
DOUSA, TP .
JOURNAL OF CLINICAL INVESTIGATION, 1982, 69 (02) :327-336
[2]  
Abboud HE, 1997, KIDNEY INT, pS3
[3]   Direct interaction of the novel nox proteins with p22phox is required for the formation of a functionally active NADPH oxidase [J].
Ambasta, RK ;
Kumar, P ;
Griendling, KK ;
Schmidt, HHHW ;
Busse, R ;
Brandes, RP .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (44) :45935-45941
[4]   ROLE OF OXIDATIVE STRESS IN DEVELOPMENT OF COMPLICATIONS IN DIABETES [J].
BAYNES, JW .
DIABETES, 1991, 40 (04) :405-412
[5]   MEAN GLOMERULAR VOLUME AND RATE OF DEVELOPMENT OF DIABETIC NEPHROPATHY [J].
BILOUS, RW ;
MAUER, SM ;
SUTHERLAND, DER ;
STEFFES, MW .
DIABETES, 1989, 38 (09) :1142-1147
[6]   Biochemistry and molecular cell biology of diabetic complications [J].
Brownlee, M .
NATURE, 2001, 414 (6865) :813-820
[7]   The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice [J].
Bueno, OF ;
De Windt, LJ ;
Tymitz, KM ;
Witt, SA ;
Kimball, TR ;
Klevitsky, R ;
Hewett, TE ;
Jones, SP ;
Lefer, DJ ;
Peng, CF ;
Kitsis, RN ;
Molkentin, JD .
EMBO JOURNAL, 2000, 19 (23) :6341-6350
[8]   The intrarenal renin-angiotensin system and diabetic nephropathy [J].
Carey, RM ;
Siragy, HM .
TRENDS IN ENDOCRINOLOGY AND METABOLISM, 2003, 14 (06) :274-281
[9]   Reactive oxygen species enhances endothelin-1 production of diabetic rat glomeruli in vitro and in vivo [J].
Chen, HC ;
Guh, JY ;
Shin, SJ ;
Tsai, JH ;
Lai, YH .
JOURNAL OF LABORATORY AND CLINICAL MEDICINE, 2000, 135 (04) :309-315
[10]   Mitochondrial function is required for hydrogen peroxide-induced growth factor receptor transactivation and downstream signaling [J].
Chen, K ;
Thomas, SR ;
Albano, A ;
Murphy, MP ;
Keaney, JF .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (33) :35079-35086