Fenofibrate attenuates tubulointerstitial fibrosis and inflammation through suppression of nuclear factor-κB and transforming growth factor-β1/Smad3 in diabetic nephropathy.
Fibrates, the ligands of peroxisome proliferator-activated receptor-alpha, have been shown to have a renal protective action in diabetic models of renal disease, but the mechanisms underlying this effect are unknown. In the present study, we sought to investigate in greater detail the effect of fenofibrate and its mechanism of action on renal inflammation and tubulointerstitial fibrosis in an animal model of type 2 diabetes mellitus. Twelve-week-old non-diabetic Zucker lean (ZL) and Zucker diabetic fatty (ZD) rats were treated with vehicle or fenofibrate for 10 weeks. mRNA and protein analyses were performed by real-time polymerase chain reaction, Western blot and immunostaining. The diabetic condition of ZD rats was associated with an increase in collagen and alpha-smooth muscle actin accumulation in the kidney, which was significantly reduced by fenofibrate. Chronic treatment of ZD rats with fenofibrate attenuated renal inflammation and tubular injury as evidenced by a decrease in mRNA and protein expression of secreted phosphoprotein-1, monocyte chemotactic protein-1 and kidney injury molecule-1 in the kidneys. Renal interstitial macrophage infiltration was also significantly reduced in the kidneys of fenofibrate-treated diabetic animals. Moreover, renal nuclear factor (NF)-kappaB DNA-binding activity, transforming growth factor (TGF)-beta1 and phospho-Smad3 proteins were significantly higher in ZD animals compared with ZL ones. This increase in NF-kappaB activity, TGF-beta1 expression and Smad3 phosphorylation was greatly attenuated by fenofibrate in the diabetic kidneys. Taken together, fenofibrate suppressed NF-kappaB and TGF-beta1/Smad3 signaling pathways and reduced renal inflammation and tubulointerstitial fibrosis in diabetic ZD animals.
Li
Lingyun
L
Department of Physiology, Atlanta, GA 30310, USA.
Emmett
Nerimiah
N
Mann
David
D
Zhao
Xueying
X
D000199:Actins / Q000378:metabolism; D000818:Animals; D003094:Collagen / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology*; D011345:Fenofibrate / Q000494:pharmacology*; D005355:Fibrosis; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009130:Muscle, Smooth / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000199:Actins; D000960:Hypolipidemic Agents; D016328:NF-kappa B; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D053773:Transforming Growth Factor beta1; D003094:Collagen; D011345:Fenofibrate
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