Inhibition of Drp1 ameliorates diabetic retinopathy by regulating mitochondrial homeostasis.
Exp Eye Res
; 220: 109095, 2022 07.
Article
in En
| MEDLINE
| ID: mdl-35490835
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Dynamins
/
Diabetes Mellitus
/
Diabetic Retinopathy
/
Mitochondria
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Exp Eye Res
Year:
2022
Document type:
Article
Country of publication:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
/
SCOTLAND
/
UK
/
UNITED KINGDOM