TY - JOUR
T1 - Fenofibrate reduces the severity of neuroretinopathy in a type 2 model of diabetes without inducing peroxisome proliferator- activated receptor alpha-dependent retinal gene expression
AU - Enright, Jennifer M.
AU - Zhang, Sheng
AU - Thebeau, Christina
AU - Siebert, Emily
AU - Jin, Alexander
AU - Gadiraju, Veda
AU - Zhang, Xiaodong
AU - Chen, Shiming
AU - Semenkovich, Clay F.
AU - Rajagopal, Rithwick
N1 - Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Fenofibrate slows the progression of clinical diabetic retinopathy (DR), but its mechanism of action in the retina remains unclear. Fenofibrate is a known agonist of peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor critical for regulating metabolism, inflammation and oxidative stress. Using a DR mouse model, db/db, we tested the hypothesis that fenofibrate slows early DR progression by activating PPARα in the retina. Relative to healthy littermates, six-month-old db/db mice exhibited elevated serum triglycerides and cholesterol, retinal gliosis, and electroretinography (ERG) changes including reduced b-wave amplitudes and delayed oscillatory potentials. These pathologic changes in the retina were improved by oral fenofibrate. However, fenofibrate did not induce PPARα target gene expression in whole retina or isolated Müller glia. The capacity of the retina to respond to PPARα was further tested by delivering the PPARα agonist GW590735 to the intraperitoneal or intravitreous space in mice carrying the peroxisome proliferator response element (PPRE)-luciferase reporter. We observed strong induction of the reporter in the liver, but no induction in the retina. In summary, fenofibrate treatment of db/db mice prevents the development of early DR but is not associated with induction of PPARα in the retina.
AB - Fenofibrate slows the progression of clinical diabetic retinopathy (DR), but its mechanism of action in the retina remains unclear. Fenofibrate is a known agonist of peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor critical for regulating metabolism, inflammation and oxidative stress. Using a DR mouse model, db/db, we tested the hypothesis that fenofibrate slows early DR progression by activating PPARα in the retina. Relative to healthy littermates, six-month-old db/db mice exhibited elevated serum triglycerides and cholesterol, retinal gliosis, and electroretinography (ERG) changes including reduced b-wave amplitudes and delayed oscillatory potentials. These pathologic changes in the retina were improved by oral fenofibrate. However, fenofibrate did not induce PPARα target gene expression in whole retina or isolated Müller glia. The capacity of the retina to respond to PPARα was further tested by delivering the PPARα agonist GW590735 to the intraperitoneal or intravitreous space in mice carrying the peroxisome proliferator response element (PPRE)-luciferase reporter. We observed strong induction of the reporter in the liver, but no induction in the retina. In summary, fenofibrate treatment of db/db mice prevents the development of early DR but is not associated with induction of PPARα in the retina.
KW - Diabetic retinopathy
KW - Electroretinography
KW - Fenofibrate
KW - Müller glia
KW - PPAR-alpha
UR - http://www.scopus.com/inward/record.url?scp=85102991609&partnerID=8YFLogxK
U2 - 10.3390/jcm10010126
DO - 10.3390/jcm10010126
M3 - Article
C2 - 33396512
AN - SCOPUS:85102991609
SN - 2077-0383
VL - 10
SP - 1
EP - 15
JO - Journal of Clinical Medicine
JF - Journal of Clinical Medicine
IS - 1
M1 - 126
ER -