20-HETE and EETs in diabetic nephropathy: a novel mechanistic pathway.
Diabetic nephropathy (DN), a major complication of diabetes, is characterized by hypertrophy, extracellular matrix accumulation, fibrosis and proteinuria leading to loss of renal function. Hypertrophy is a major factor inducing proximal tubular epithelial cells injury. However, the mechanisms leading to tubular injury is not well defined. In our study, we show that exposure of rats proximal tubular epithelial cells to high glucose (HG) resulted in increased extracellular matrix accumulation and hypertrophy. HG treatment increased ROS production and was associated with alteration in CYPs 4A and 2C11 expression concomitant with alteration in 20-HETE and EETs formation. HG-induced tubular injury were blocked by HET0016, an inhibitor of CYPs 4A. In contrast, inhibition of EETs promoted the effects of HG on cultured proximal tubular cells. Our results also show that alteration in CYPs 4A and 2C expression and 20HETE and EETs formation regulates the activation of the mTOR/p70S6Kinase pathway, known to play a major role in the development of DN. In conclusion, we show that hyperglycemia in diabetes has a significant effect on the expression of Arachidonic Acid (AA)-metabolizing CYPs, manifested by increased AA metabolism, and might thus alter kidney function through alteration of type and amount of AA metabolites.
Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
Stephanie
S
Eid
Rita
R
Maalouf
Ayad A
AA
Jaffa
Joseph
J
Nassif
Ahmed
A
Hamdy
Awad
A
Rashid
Fuad N
FN
Ziyadeh
Assaad A
AA
Eid
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D006984:Hypertrophy / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D006893:Hydroxyeicosatetraenoic Acids; D017382:Reactive Oxygen Species; C400322:cytochrome P-450 CYP2C subfamily; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D042926:Cytochrome P-450 CYP4A; C546845:mTOR protein, rat; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D015126:8,11,14-Eicosatrienoic Acid; D005947:Glucose