June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Down-Regulation of PPARα through MicroRNA-Associated Mechanism in Diabetic Retinopathy
Author Affiliations & Notes
  • Yusuke Takahashi
    Medicine-Endocrinology, Univ of Oklahoma Hlth Sci Ctr, Oklahoma City, Oklahoma, United States
    Harold Hamm Diabetes Center, Oklahoma City, Oklahoma, United States
  • Qian Chen
    Physiology, Univ of Oklahoma Hlth Sci Ctr, Oklahoma City, Oklahoma, United States
    Harold Hamm Diabetes Center, Oklahoma City, Oklahoma, United States
  • Fangfang Qiu
    Physiology, Univ of Oklahoma Hlth Sci Ctr, Oklahoma City, Oklahoma, United States
  • H. Greg Matlock
    Physiology, Univ of Oklahoma Hlth Sci Ctr, Oklahoma City, Oklahoma, United States
    Harold Hamm Diabetes Center, Oklahoma City, Oklahoma, United States
  • Elizabeth P Moran
    Physiology, Univ of Oklahoma Hlth Sci Ctr, Oklahoma City, Oklahoma, United States
    Harold Hamm Diabetes Center, Oklahoma City, Oklahoma, United States
  • Raju V S Rajala
    Ophthal/Dean McGee Eye Inst, Univ of Oklahoma Hlth Sci Ctr, Oklahoma City, Oklahoma, United States
    Physiology, Univ of Oklahoma Hlth Sci Ctr, Oklahoma City, Oklahoma, United States
  • Jian-Xing (Jay) Ma
    Physiology, Univ of Oklahoma Hlth Sci Ctr, Oklahoma City, Oklahoma, United States
    Harold Hamm Diabetes Center, Oklahoma City, Oklahoma, United States
  • Footnotes
    Commercial Relationships   Yusuke Takahashi, None; Qian Chen, None; Fangfang Qiu, None; H. Greg Matlock, None; Elizabeth Moran, None; Raju Rajala, None; Jian-Xing (Jay) Ma, None
  • Footnotes
    Support  NIH grants (EY018659, EY012231, EY019309, P20GM104934), a JDRF grant (2-SRA-2014-147-Q-R), American Heart Association (14PRE20460229), an IRRF grant and OCAST grants (HR13-076)
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 5214. doi:
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    • Get Citation

      Yusuke Takahashi, Qian Chen, Fangfang Qiu, H. Greg Matlock, Elizabeth P Moran, Raju V S Rajala, Jian-Xing (Jay) Ma; Down-Regulation of PPARα through MicroRNA-Associated Mechanism in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5214.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Peroxisome proliferator-activated receptor-alpha (PPARα) is a crucial transcription factor regulating numerous gene expressions implicated in lipid metabolism, glucose metabolism and insulin resistance. Two longitudinal clinical studies reported that administration of fenofibrate, a specific PPARα agonist, showed robust beneficial effects on diabetic retinopathy (DR) in type 2 diabetes patients. Our recent studies showed that PPARα possesses anti-inflammatory and anti-apoptotic functions, and down-regulation of PPARα in diabetic retina is associated with pathogenic features of DR. In the last ARVO meeting, we reported that over-expression of microRNA-21 (miR-21) is implicated in the PPARα down-regulation in DR. In the present study, we examined the functional role of miR-21 in retinal inflammation and retinal cell apoptosis due to the down-regulation of PPARα in DR.

Methods : PPARα expression, inflammation and apoptosis in the retina of 6 month-old db/db and double knockout (dKO; Leptin receptor (db/db) and miR-21) mice were examined by qRT-PCR, Western blotting and ELISA. Similarly, miR-21 inhibitor and its negative control inhibitor were packed in nanoparticle and injected into vitreous space of 5 month-old db/db mice, and PPARα expression, retinal inflammation and retinal cell apoptosis were evaluated at 6 month-old. Furthermore, in addition to retinal inflammation, the impact of miR-21 on retinal neovascularization was evaluated with oxygen-induced retinopathy (OIR) model using miR-21 KO mice.

Results : Expression levels of PPARα were significantly higher in the retina of dKO mice, whereas retinal inflammation and retinal cell apoptosis were significantly lower compared to age-matched db/db mice. Similarly, delivery of miR-21 inhibitor into vitreous space prevented the down-regulation of PPARα and reduced retinal inflammation and apoptosis. Furthermore, retinal neovascularization and retinal inflammation were ameliorated in the retina of miR-21 KO mice with OIR.

Conclusions : The present study showed that diabetes-induced over-expression of miR-21 in the retina is responsible, at least in part, for down-regulation of PPARα in DR. Our studies also suggest that knock-down of miR-21 in the retina offers a therapeutic benefit to ameliorate inflammatory responses, oxidative stress and neuronal apoptosis in DR.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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