Abstract:Empagliflozin (EMPA) is a novel sodium-glucose cotransporter 2 inhibitor (SGLT2i) that produces protective cardiovascular-renal outcomes in patients with diabetes. However, the effects of EMPA on obesity-related kidney disease have not been determined. The heme oxygenase-1 (HO-1)–adiponectin axis is an essential antioxidant system with anti-apoptotic and anti-inflammatory properties. This study explored whether EMPA improves obesity-related kidney disease through regulation of the renal HO-1-mediated adiponect… Show more
“…It has been demonstrated in multiple animal experiments that SGLT2i can improve the terminal outcome of the kidney by promoting autophagy or improving related inflammation [ 22 , 23 ]. Similar effects on improving the inflammatory response were observed in models of infectious kidney injury and oxidative damage [ 24 , 25 ], which might be achieved by reducing the activity of NLRP3 inflammasomes [ 26 , 27 ]. In addition, autophagy may be improved through the mTOR1-related signaling pathway [ 28 ].…”
Section: Sglt2i Provide Renal Protection In Animal Modelsmentioning
Diabetic kidney disease (DKD) is one of the most important comorbidities for patients with diabetes, and its incidence has exceeded one tenth, with an increasing trend. Studies have shown that diabetes is associated with a decrease in the number of podocytes. Diabetes can induce apoptosis of podocytes through several apoptotic pathways or induce autophagy of podocytes through related pathways. At the same time, hyperglycemia can also directly lead to apoptosis of podocytes, and the related inflammatory reactions are all harmful to podocytes. Podocyte damage is often accompanied by the production of proteinuria and the progression of DKD. As a new therapeutic agent for diabetes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been demonstrated to be effective in the treatment of diabetes and the improvement of terminal outcomes in many rodent experiments and clinical studies. At the same time, SGLT2i can also play a protective role in diabetes-induced podocyte injury by improving the expression of nephrotic protein defects and inhibiting podocyte cytoskeletal remodeling. Some studies have also shown that SGLT2i can play a role in inhibiting the apoptosis and autophagy of cells. However, there is no relevant study that clearly indicates whether SGLT2i can also play a role in the above pathways in podocytes. This review mainly summarizes the damage to podocyte structure and function in DKD patients and related signaling pathways, as well as the possible protective mechanism of SGLT2i on podocyte function.
“…It has been demonstrated in multiple animal experiments that SGLT2i can improve the terminal outcome of the kidney by promoting autophagy or improving related inflammation [ 22 , 23 ]. Similar effects on improving the inflammatory response were observed in models of infectious kidney injury and oxidative damage [ 24 , 25 ], which might be achieved by reducing the activity of NLRP3 inflammasomes [ 26 , 27 ]. In addition, autophagy may be improved through the mTOR1-related signaling pathway [ 28 ].…”
Section: Sglt2i Provide Renal Protection In Animal Modelsmentioning
Diabetic kidney disease (DKD) is one of the most important comorbidities for patients with diabetes, and its incidence has exceeded one tenth, with an increasing trend. Studies have shown that diabetes is associated with a decrease in the number of podocytes. Diabetes can induce apoptosis of podocytes through several apoptotic pathways or induce autophagy of podocytes through related pathways. At the same time, hyperglycemia can also directly lead to apoptosis of podocytes, and the related inflammatory reactions are all harmful to podocytes. Podocyte damage is often accompanied by the production of proteinuria and the progression of DKD. As a new therapeutic agent for diabetes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been demonstrated to be effective in the treatment of diabetes and the improvement of terminal outcomes in many rodent experiments and clinical studies. At the same time, SGLT2i can also play a protective role in diabetes-induced podocyte injury by improving the expression of nephrotic protein defects and inhibiting podocyte cytoskeletal remodeling. Some studies have also shown that SGLT2i can play a role in inhibiting the apoptosis and autophagy of cells. However, there is no relevant study that clearly indicates whether SGLT2i can also play a role in the above pathways in podocytes. This review mainly summarizes the damage to podocyte structure and function in DKD patients and related signaling pathways, as well as the possible protective mechanism of SGLT2i on podocyte function.
“…Consistent with our previous study, the HFD-induced metabolic disturbance was improved by EMPA treatment (p < 0.05). 18 , 20 Figure 1 Mouse biochemistry parameters (A–J) (A) body weight, (B) fat mass, (C) fat/body weight, (D) serum triglyceride, (E) fasting glucose, (F) fasting insulin, (G) homeostatic model assessment of insulin resistance (HOMA-IR) index, (H) free fatty acids (FFA), (I) oral glucose tolerance test (OGTT), and (J) insulin tolerance test (ITT) curve. ∗p < 0.05, ∗∗p < 0.01, for (E) and (F), ∗HFD vs. CT p < 0.05, # EMPA vs. HFD, n = 5–6.…”
Section: Resultsmentioning
confidence: 99%
“…We previously demonstrated that EMPA can protect against obesity-related cardiac dysfunction, nonalcoholic fatty liver disease, and chronic kidney disease via different mechanisms. 18 , 19 , 20 This protection was associated with improving metabolic disruption, including a reduced fat/body weight ratio and restored glucose homeostasis. Our study further confirmed that EMPA can reduce the fat/body weight ratio and alleviate impaired glucose/insulin tolerance.…”
Section: Discussionmentioning
confidence: 98%
“… 16 , 17 Our previous work showed that EMPA can improve obesity-related complications, including cardiac dysfunction, nonalcoholic fatty liver disease, and chronic kidney disease. 18 , 19 , 20 …”
“…Regulatory effects of SGLT-2i have been implicated in ER and oxidative stress, autophagy, apoptosis, and inflammation [ 96 ]. Ye, T. et al treated HFD-fed C57BL/6J mice with empagliflozin and found that empagliflozin reduced fat mass, body weight, plasma TG and FFA levels, fasting glucose levels, and NLRP3 inflammasome activity, and induced HO-1-adiponectin-dependent signaling pathway [ 97 ].…”
Metabolic associated fatty liver disease (MAFLD) is one of the most common causes of chronic liver disease worldwide. To date, there is no FDA-approved treatment, so there is an urgent need to determine its pathophysiology and underlying molecular mechanisms. Autophagy is a lysosomal degradation pathway that removes damaged organelles and misfolded proteins after cell injury through endoplasmic reticulum stress or starvation, which inhibits apoptosis and promotes cell survival. Recent studies have shown that autophagy plays an important role in removing lipid droplets from hepatocytes. Autophagy has also been reported to inhibit the production of pro-inflammatory cytokines and provide energy for the hepatic stellate cells activation during liver fibrosis. Thyroid hormone, irisin, melatonin, hydrogen sulfide, sulforaphane, DA-1241, vacuole membrane protein 1, nuclear factor erythroid 2-related factor 2, sodium-glucose co-transporter type-2 inhibitors, immunity-related GTPase M, and autophagy-related gene 7 have been reported to ameliorate MAFLD via autophagic induction. Lipid receptor CD36, SARS-CoV-2 Spike protein and leucine aminopeptidase 3 play a negative role in the autophagic function. This review summarizes recent advances in the role of autophagy in MAFLD. Autophagy modulates major pathological changes, including hepatic lipid metabolism, inflammation, and fibrosis, suggesting the potential of modulating autophagy for the treatment of MAFLD.
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