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  2. Destruction of the blood-retina barrier in diabetic retinopathy depends on angiotensin-converting enzyme-mediated TGF-β1/Smad signaling pathway activation

Destruction of the blood-retina barrier in diabetic retinopathy depends on angiotensin-converting enzyme-mediated TGF-β1/Smad signaling pathway activation

  • Int Immunopharmacol. 2020 Aug;85:106686. doi: 10.1016/j.intimp.2020.106686.
Ping Sun 1 Ning Xu 2 Yan Li 3 Yang Han 3
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Haerbin Fifth Hospital, Haerbin, China. Electronic address: sunping1977y@163.com.
  • 2 Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.
  • 3 Department of Ophthalmology, Haerbin Fifth Hospital, Haerbin, China.
Abstract

Diabetes mellitus (DM) is a systemic, chronic Metabolic Disease that is related to heredity and autoimmunity and is often accompanied by complications of retinopathy. However, the causative mechanism involved in the pathological process remains unclear. In this research, treatment with fosinopril or LY2109761 was found to be responsible for the improvement of the pathological processes, serum biochemical indexes and retinopathy in rats with streptozotocin-induced diabetes. In addition, the upregulation of angiotensin-converting Enzyme (ACE) in the serum and the increased expression of TGF-β1 in the pathological outer nuclear layer (ONL) and inner nuclear layer (INL) of the retina were also reduced. In vitro experiments demonstrated that ACE enhanced cell damage and TGF-β1/Smad signaling pathway activation in retinal capillary endothelial cells (RCECs) under high glucose conditions. In addition, the activity of ACE was also considered to be related to the increasing levels of activated TGF-β1 in both rat retinal Müller cells (RMCs) and RCECs, but ACE activity had no effect on the high glucose-mediated upregulation of total TGF-β1 in RMCs. Coculture experiments with RCECs and RMCs showed that the barrier that was established under normal conditions was significantly impaired when exposed to high glucose combined with ACE, and damage of barrier can be prevented by adding fosinopril or LY2109761. Finally, a similar auxiliary effect of ACE was also observed in the activated TGF-β1-mediated barrier damage in blood-retinal barrier model in vitro. In summary, ACE-mediated TGF-β1/Smad signaling pathway activation was found to be involved in the destruction of the blood-retina barrier during diabetic retinopathy in a model of streptozotocin-induced diabetes, and these data may provide evidence to guide the treatment of the complications of diabetes mellitus.

Keywords

Angiotensin-Converting Enzyme; Diabetes mellitus; Diabetic Retinopathy; Streptozotocin; TGF-β1/Smad signaling pathway.

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