Inhibition of Drp1 ameliorates diabetic retinopathy by regulating mitochondrial homeostasis.

Abstract

Diabetic retinopathy (DR) is a potentially blinding complication resulting from diabetes mellitus (DM). Retinal vascular endothelial cells (RMECs) dysfunction occupies an important position in the pathogenesis of DR, and mitochondrial disorders play a vital role in RMECs dysfunction. However, the detailed mechanisms underlying DR-induced mitochondrial disorders in RMECs remain elusive. In the present study, we used High glucose (HG)-induced RMECs in vitro and streptozotocin (STZ)-induced Sprague-Dawley rats in vivo to explore the related mechanisms. We found that HG-induced mitochondrial dysfunction via mitochondrial Dynamin-related protein 1(Drp1)-mediated mitochondrial fission. Drp1 inhibitor, Mdivi-1, rescued HG-induced mitochondrial dysfunction. Protein Kinase Cδ (PKCδ) could induce phosphorylation of Drp1, and we found that HG induced phosphorylation of PKCδ. PKCδ inhibitor (Go 6983) or PKCδ siRNA reversed HG-induced phosphorylation of Drp1 and further mitochondrial dysfunction. The above studies indicated that HG increases mitochondrial fission via promoting PKCδ/Drp1 signaling. Drp1 induces excessive mitochondrial fission and produces damaged mitochondrial, and mitophagy plays a key role in clearing damaged mitochondrial. Our study showed that HG suppressed mitophagy via inhibiting LC3B-II formation and p62 degradation. 3-MA (autophagy inhibitor) aggravated HG-induced RMECs damage, while rapamycin (autophagy agonist) rescued the above phenomenon. Further studies were identified that HG inhibited mitophagy by down-regulation of the PINK1/Parkin signaling pathway, and PINK1 siRNA aggravated HG-induced RMECs damage. Further in-depth study, we propose that Drp1 promotion of Hexokinase II (HK-II) separation from mitochondria, thus inhibiting HK-II-PINK1-mediated mitophagy. In vivo, we found that intraretinal microvascular abnormalities (IRMA), including retinal vascular leakage, acellular capillaries, and apoptosis were increased in STZ-induced DR rats, which were reversed by pretreatment with Mdivi-1 or Rapamycin. Altogether, our findings provide new insight into the mechanisms underlying the regulation of mitochondrial homeostasis and provide a potential treatment strategy for Diabetic retinopathy.

• Authors: Meng-Yuan Zhang, Lingpeng Zhu, Xun Bao, Tian-Hua Xie, Jiping Cai, Jian Zou, Wenjuan Wang, Shun Gu, Yan Li, Hong-Ying Li, Yong Yao, Ting-Ting Wei
• Journal: Experimental eye research (Exp Eye Res) Vol. 220 Pg. 109095 (07 2022) ISSN: 1096-0007 [Electronic] England
• PMID: 35490835 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• RNA, Small Interfering
• Protein Kinases
• Dnm1l protein, rat
• Dynamins
• Sirolimus

Topics

• Animals
• Diabetes Mellitus (metabolism)
• Diabetic Retinopathy (metabolism)
• Dynamins (antagonists & inhibitors, metabolism)
• Endothelial Cells (metabolism)
• Homeostasis
• Mitochondria (metabolism)
• Protein Kinases (genetics, metabolism)
• RNA, Small Interfering
• Rats
• Rats, Sprague-Dawley
• Sirolimus