Calcium Dobesilate Restores Autophagy by Inhibiting the VEGF/PI3K/AKT/mTOR Signaling Pathway

Abstract

Objective: Calcium dobesilate (CaD), an effective drug for the treatment of diabetic microvascular complications, especially diabetic retinopathy, is widely used in the clinic. Interestingly, several studies have indicated that CaD is therapeutic for diabetic kidney disease (DKD). Recently, evidence has indicated that altered vascular endothelial growth factor (VEGF) expression and decreased autophagy are the main pathological mechanisms of proteinuria. Thus, this study was conducted to explore the effect of CaD on restoring autophagy in DKD and the possible signaling pathway between VEGF and autophagy. Methods: Obese mice with spontaneous diabetes (KK-Ay) and high-fat diet- and streptozotocin-induced diabetic mice (HFD/STZ) were used in this study. Biochemical staining, western blotting, and immunohistochemistry were conducted to determine the angioprotective effect of CaD and the underlying mechanism between autophagy and VEGF/VEGFR. Results: Our results showed that CaD was capable of reducing albuminuria and restoring renal histological changes in KK-Ay and HFD/STZ-induced diabetic mice. CaD restored autophagy by decreasing the protein expression of LC3 II, Atg5, and beclin 1 and increasing the expression of P62. Moreover, CaD reduced the activation of the autophagy-related PI3K/AKT/mTOR pathway possibly via decreasing VEGF and downregulating VEGF receptor 2. Conclusion: Overall, CaD, as a novel potential therapeutic drug for DKD, plays a key role in protecting renal function and restoring autophagy by blocking VEGF/VEGFR2 and inhibiting the PI3K/AKT/mTOR signaling pathway.

Effect of Calcium Dobesilate (CaD) on Diabetic Macular Edema Treated by Intravitreal Ranibizumab

“…CaD (calcium 2,5-dihydroxybenzenesulfonate) is a vascular protective drug which has been proved to have bene cial effects in vascular diseases such as chronic venous insu ciency and haemorrhoids [27] and is extensively used to treat diabetic retinopathy [28][29][30], choronic venous insu ciency [31] and multiple microangiopathic diseases [32]. In previous studies, the potential mechanisms of CaD improving microcirculation and reducing micro-vascular injury had been investigated as follows [21]: (1) reducing platelet aggregation caused by thrombin or collagen [33]; (2) signi cantly protecting peritoneal vascular from reactive oxygen species (ROS) effects of penetration [34]; (3) inhibiting capillary permeability [35]; (4) alleviating the chronic in ammatory state and improving endothelial cell function [36,37]; (5) reducing endothelial shedding by the synthesis and release of nitric oxide (NO) [38]; (6) reducing platelet aggregation by inhibiting prostaglandin and reduce erythrocyte aggregation and viscosity of suspension [24]; (7) down-regulating the expression of VEGF and broblast growth factor (FGF) to inhibit vascular endothelial cell proliferation [39]; (8) restoring autophagy by inhibiting the VEGF/PI3K/AKT/mTOR signaling pathway [40]. Therefore, based on these mechanisms mentioned above, CaD should be effective in the treatment of macular edema.…”

Enhanced Autophagic Flux, Suppressed Apoptosis and Reduced Macrophage Infiltration by Dasatinib in Kidneys of Obese Mice

“…OD also increased renal lipogenesis marker SREBP1 [ 40 ] and renal inflammatory macrophage proinflammatory markers iNOS and CD68 in kidney tissues [ 3 ]. Furthermore, defective autophagy was confirmed by decreased LC3 and increased P62 expressions [ 10 ]. Moreover, it was associated with an elevation in renal fibrosis markers: TGF-β, PDGFA [ 5 ] and ASMA [ 6 ].…”

“…Altered autophagy in vascular endothelium, epithelium, pericytes, podocytes and mesangium results in imbalance in cell homeostasis. ORC was reported to be associated with suppressed renal autophagy [ 10 ].…”

Mingmu Xiaomeng Tablets Restore Autophagy and Alleviate Diabetic Retinopathy by Inhibiting PI3K/Akt/mTOR Signaling

“…Previous study indicates PI3K/Akt/mTOR signaling pathway is hyperactivated in human cancers (Ersahin et al, 2015;Tewari et al, 2019). New studies have found that PI3K/Akt/mTOR proteins are widely expressed in the retinal tissue of diabetic rats (Wang et al, 2019;He et al, 2020). Therefore, inhibition of PI3K/Akt/mTOR is a target for the treatment of diabetic retinopathy.…”

“…Calcium dobesilate (calcium 2,5-dihydroxybenzenesulfonic acid; CD) was registered by the European Pharmacopoeia and British Pharmacopoeia in 1997 and 1998, respectively (Zhang et al, 2015). It is considered an angioprotective agent with antiinflammatory, antioxidative, and anti-angiogenic properties (Wang et al, 2019) and prescribed as an alternative therapy for the treatment of diabetic retinopathy and other vascular disorders (Berthet et al, 1999;Rabe et al, 2011). CD is indicated and approved for the treatment of DR in several countries, and it is beneficial in the early stages of DR (Simó et al, 2015).…”