Glomerular 20-HETE, EETs, and TGF-beta1 in diabetic nephropathy.
The early stage of diabetic nephropathy (DN) is linked to proteinuria. Transforming growth factor (TGF)-beta1 increases glomerular permeability to albumin (P(alb)), whereas 20-HETE and EETs reduce P(alb). To investigate the impact of hyperglycemia and hyperlipidemia on 20-HETE, EETs, and TGF-beta1 in the glomeruli, rats were divided into four groups: ND rats were fed a normal diet, HF rats were fed a high-fat diet, STZ rats were treated with 35 mg/kg of streptozotocin, and HF/STZ rats were fed a HF diet and treated with STZ. After 10 wk on these regimens, blood glucose, urinary albumin, serum cholesterol, serum triglyceride levels, and the kidney-to-body weight ratio were significantly elevated in STZ and HF/STZ rats compared with HF and ND rats. STZ and HF/STZ rats had histopathologic changes and abnormal renal hemodynamics. Expression of glomerular CYP4A, enzymes for 20-HETE production, was significantly decreased in STZ rats, whereas expression of glomerular CYP2C and CYP2J, enzymes for EETs production, was significantly decreased in both STZ and HF/STZ rats. Moreover, glomerular TGF-beta1 levels were significantly greater in STZ and HF/STZ rats than in HF and ND rats. Five-week treatment of STZ rats with clofibrate induced glomerular CYP4A expression and 20-HETE production, but reduced glomerular TGF-beta1 and urinary protein excretion. These results demonstrate that hyperglycemia increases TGF-beta1 but decreases 20-HETE and EETs production in the glomeruli, changes that may be important in causing glomerular damage in the early stage of DN.
Luo
Pengcheng
P
Department of Physiology, Medical College of Georgia, Augusta, Georgia 30912, USA.
Zhou
Yiqiang
Y
Chang
Hsin-Hsin
HH
Zhang
Jie
J
Seki
Tsugio
T
Wang
Cong-Yi
CY
Inscho
Edward W
EW
Wang
Mong-Heng
MH
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002994:Clofibrate; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D004851:Epoxide Hydrolases / Q000378:metabolism; D004852:Epoxy Compounds / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism; D006949:Hyperlipidemias / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism*; D008297:Male; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000378:metabolism; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation; D013311:Streptozocin; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D000596:Amino Acids; D004852:Epoxy Compounds; D006893:Hydroxyeicosatetraenoic Acids; D020033:Protein Isoforms; D053773:Transforming Growth Factor beta1; D013311:Streptozocin; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D042926:Cytochrome P-450 CYP4A; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid; D002994:Clofibrate