Endoplasmic reticulum (ER) and mitochondrial dysfunction play fundamental roles in the pathogenesis of diabetic retinopathy (DR). However, the interrelationship between the ER and mitochondria are poorly understood in DR. Here, we established high glucose (HG) or advanced glycosylation end products (AGE)-induced human retinal vascular endothelial cell (RMEC) models in vitro, as well as a streptozotocin (STZ)-induced DR rat model in vivo. Our data demonstrated that there was increased ER–mitochondria coupling in the RMECs, which was accompanied by elevated mitochondrial calcium ions (Ca2+) and mitochondrial dysfunction under HG or AGE incubation. Mechanistically, ER–mitochondria coupling was increased through activation of the IP3R1–GRP75–VDAC1 axis, which transferred Ca2+ from the ER to the mitochondria. Elevated mitochondrial Ca2+ led to an increase in mitochondrial ROS and a decline in mitochondrial membrane potential. These events resulted in the elevation of mitochondrial permeability and induced the release of cytochrome c from the mitochondria into the cytoplasm, which further activated caspase-3 and promoted apoptosis. The above phenomenon was also observed in tunicamycin (TUN, ER stress inducer)-treated cells. Meanwhile, BAPTA-AM (calcium chelator) rescued mitochondrial dysfunction and apoptosis in DR, which further confirmed of our suspicions. In addition, 4-phenylbutyric acid (4-PBA), an ER stress inhibitor, was shown to reverse retinal dysfunction in STZ-induced DR rats in vivo. Taken together, our findings demonstrated that DR fueled the formation of ER–mitochondria coupling via the IP3R1–GRP75–VDAC1 axis and accelerated Ca2+-dependent cell apoptosis. Our results demonstrated that inhibition of ER–mitochondrial coupling, including inhibition of GRP75 or Ca2+ overload, may be a potential therapeutic target in DR.

Summary Background Coronavirus disease 2019 (COVID-19) infection has caused huge impacts on all of people’s lives and health systems. In response to the COVID-19 pandemic, China was the first country to impose lockdown. We aimed to study the influence of COVID-19 on the outpatient visits of rheumatic patients in a non-outbreak area of China. Methods We selected three provincial or ministerial hospitals in Jinan, and collected the outpatient appointments data in rheumatology and immunology departments during the Shandong Province first-level public health emergency response period from 25 January 2020 to 8 March 2020. Results In the early stage, the number of outpatient appointments in the rheumatology and immunology departments of the three provincial or ministerial hospitals were significantly reduced, and gradually restored in the late stage. It showed that in the face of major infectious diseases, strict quarantine measures with the cooperation of the public not only controls the epidemic in a short time, but also lifts the quarantine measures and opens general outpatient clinics in hospitals as soon as possible, thus minimizing the impact on other patients. Interpretation The impact on the western hospital was greater than that on the Chinese medicine hospital, and the impact on the back-up designated hospitals for COVID-19 was the greatest. Online appointment can reduce the risk of infection in outpatients, but not completely solve the follow-up problem of rheumatic patients. Telemedicine provides a new solution for both management of rheumatic patients and control of COVID-19.

Background Endoplasmic reticulum (ER) and mitochondrial dysfunction play fundamental roles in the pathogenesis of diabetic retinopathy (DR). The communication between the mitochondria and the ER is mediated by a functional subdomain referred to as the mitochondria-associated membrane (MAM). However, the mechanism underlying material exchange between the ER and mitochondria are poorly understood. This study aimed to explore the role of IP3R1-GRP75-VDAC1 axis in modulating Ca2+ homeostasis in RMECs. Methods In this study, we established high glucose (HG) and advanced glycosylation end products (AGEs)-induced human retinal vascular endothelial cells (RMECs) models in vitro, and streptozotocin (STZ)-induced DR model in vivo. CCK8 assay and Calcein-AM/PI double stain were used to detect cell viability.The ER-Tracker Red Kit and MitoTracker-Green are used to co-localize ER and mitochondria. Mitochondrial Ca2+ was detected using Rhod-2 AM. Co-immunoprecipitation (co-IP) was used to examine the interaction between IP3R1, GRP75 and VDAC1. MitoSOX™ Red Probe, mPTP Assay, and JC-1 Assay are used to measure mitochondrial function. Evans blue dye, retinal PAS staining, and TUNEL assay were used to assess retinal function. Results Our data demonstrated that there was increased ER-mitochondria coupling in the RMECs, which was accompanied by elevated mitochondrial calcium ions (Ca2+) and mitochondrial dysfunction (mitochondrial membrane potential, ΔΨm; and mitochondrial ROS) under HG or AGEs transferred ER Ca2+ into the mitochondria. Elevated mitochondrial Ca2+ concentrations led to an increase in mitochondrial ROS and a decline in mitochondrial membrane potential. These events resulted in mitochondrial dysfunction and elevation of mitochondrial permeability, which induced cytoplasmic Cyt c/Caspase-3-mediated cell apoptosis. The above phenomenon was reversed by BAPTA-AM (an intracellular calcium chelator) and tunicamycin (TUN), a common ERS inducer. In addition, 4-PBA, (an ERS inhibitor), was shown to reverse retinal dysfunction in STZ-induced DR rats. Conclusions Our findings demonstrated that DR fuels the formation of ER-mitochondria coupling via the IP3R1-GRP75-VDAC1 axis, which facilitates transport of Ca2+ from the ER to the mitochondria, eventually leading to mitochondrial dysfunction and apoptosis of endothelial cells. Our results demonstrated that inhibition of ER-mitochondrial coupling, including inhibition of GRP75 or Ca2+ overload, may be a potential therapeutic target in DR.