Calcium Dobesilate Prevents Diabetic Kidney Disease by Decreasing Bim and Inhibiting Apoptosis of Renal Proximal Tubular Epithelial Cells

et al. 2018

Front. Pharmacol.

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Background: Accumulating evidences indicate that the apoptosis of proximal tubular epithelial cells (PTECs) play a vital role in the progression of the diabetic kidney disease (DKD). This study aimed to explore the therapeutic potential of salidroside (SAL) in DKD and its underlying mechanism in anti-apoptosis of PTECs.Methods: Twenty-eight male Wistar rats were allocated into four groups: sham-operated, uninephrectomy (unx), diabetes with uninephrectomy (DKD) and DKD treated with SAL (DKD + SAL). SAL (70 mg/kg) was gavage administered for 8 weeks. 24-h albuminuria and serum creatinine (SCr), blood urea nitrogen (BUN), renal histological changes were examined. The silico analysis was used to identify the main therapeutic targets and pathways of SAL involved in DKD treatment. Apoptosis was determined by TUNEL and Annexin V-FITC/PI double staining in vivo and in vitro, respectively. The expression of BIM, BAX, and cleaved caspase-3 were evaluated by western blot and immunostaining.Results: Treatment with SAL significantly attenuated diabetic kidney injury via inhibiting 24-h albuminuria, SCr, BUN, glomerular mesangial dilatation and tubular injury in DKD rats. The silico analysis identified the intrinsic apoptotic pathway as an important pathway responsible for the nephroprotective properties of SAL. Our data validated that SAL effectively inhibited the apoptosis of PTECs induced by high-glucose (HG), both in vitro and in vivo. Silence of BIM by shRNA in HK-2 cells prevented HG-induced apoptosis. The up-regulated BIM and its downstream targets (BAX and cleaved caspase-3) were also inhibited by SAL.Conclusion: In summary, SAL significantly relieved DKD. And the possible mechanisms might be partially attributed to inhibiting apoptosis of proximal renal tubular cells. The apoptotic protein BIM could be an important target of SAL in this process.

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Protective Effect of Salidroside Against Diabetic Kidney Disease Through Inhibiting BIM-Mediated Apoptosis of Proximal Renal Tubular Cells in Rats

Guo

et al. 2018

Front. Pharmacol.

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“…This study also showed that Hyp could improve the function of pancreatic islets, increase glycolysis, and decrease gluconeogenesis. Regarding to diabetes-related complications, the protective effects of Hyp had been shown on diabetic nephropathy at early stage in a STZ induced-diabetic mouse model (Cai et al, 2017). Our previous results showed that Hyp could reduce the damage of isolated rat retinal vascular endothelial cells (RVECs) induced by H 2 O 2 (Wu et al, 2013).…”

Section: Introductionmentioning

confidence: 98%

“…Currently, anti-vascular endothelial growth factor (VEGF) reagents and corticosteroids are broadly used in the clinic for treating this disease (Singer et al, 2016). Calcium dobesilate, which is an established vasoactive and angioprotective drug, has been used to treat diabetic retinopathy at the systematic and local ocular level with promising results (Haritoglou et al, 2009;Cai et al, 2017). However, these drugs may show some side effects, and not all patients respond to anti-VEGF agents.…”

Section: Introductionmentioning

confidence: 99%

Hyperoside Ameliorates Diabetic Retinopathy via Anti-Oxidation, Inhibiting Cell Damage and Apoptosis Induced by High Glucose

Xie

et al. 2020

Front. Pharmacol.

Background: Hyperoside (Hyp) is a flavonoid substance extracted from plants, which has the functions of anti-cancer, anti-inflammatory, and anti-oxidation. In the previous study, we found that Hyp reduced the injury of rat retinal vascular endothelial cells (RVECs) induced by H 2 O 2. Method: In the present research, we evaluated the protective effect of Hyp on the pathological damage of retina caused by high glucose of diabetes mellitus (DM) in in vitro and in vivo experiments. The effect of Hyp on cell viability, oxidative stress level, and apoptosis of RVECs was assessed. Results: Hyp significantly reduced the of RVECs damage, oxidative stress level, and cell apoptosis induced by high glucose in vitro. In DM model rats, Hyp treatment could significantly reduce blood glucose levels and the pathological damage of retina caused by DM and increase the proliferation of RVECs while exerting the inhibition on apoptotic activity. Furthermore, Hyp treatment decreased the expressions of apoptotic proteins including caspase-3, caspase-9, and Bax in RVECs of DM rats, while increased the expression of anti-apoptotic protein Bcl-2. Conclusion: Hyp may have protective effect on diabetes-induced retinopathy by reducing oxidative stress, inhibiting cell damage, and apoptosis induced by high glucose.

“…Apoptosis has been found in proximal renal tubules and distal renal tubules in diabetic patients [ 9 ]. In addition, DKD animals and proximal renal tubular cells in vitro undergo apoptosis in a high-glucose (HG) environment [ 10 , 11 ]. From this evidence, we can consider the apoptosis of tubular cells to be a vital feature of DKD [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin E1 attenuates high glucose-induced apoptosis in proximal renal tubular cells by inhibiting the JNK/Bim pathway

Guo

et al. 2019

Acta Pharmacol Sin

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Proximal renal tubular damage is a critical process underlying diabetic kidney disease (DKD). Our previous study shows that prostaglandin E1 (PGE1) reduces the apoptosis of renal tubular cells in DKD rats. But its underlying mechanisms remain unclear. In this study we investigated the protective effects of PGE1 in DKD rats and high glucose (HG, 30 mM)-treated HK-2 proximal tubular cells. Four weeks after uninephrectomized streptozotocin-induced diabetic rats were established, the DKD rats were administered PGE1 (10 µg· kg −1 · d −1 , iv.) for 10 consecutive days. We showed that PGE1 administration did not change blood glucose levels, but alleviated diabetic kidney injury in the DKD rats, evidenced by markedly reduced proteinuria and renal tubular apoptosis. In the in vitro experiments, PGE1 (0.1–100 µM) significantly enhanced HG-reduced HK-2 cell viability. In HG-treated HK-2 cells, PGE1 (10 µM) significantly suppressed the c-Jun N-terminal kinase (JNK) and the mitochondrial apoptosis-related protein expressions such as Bim, Bax, caspase-3 and cleaved caspase-3; similar changes were also observed in the kidney of PGE1-treated DKD rats. By using two pharmacological tools-JNK activator anisomycin (AM) and JNK inhibitor SP600125, we revealed that PGE1 blocked HG-triggered activation of JNK/Bim pathway in HK-2 cells; JNK was an upstream regulator of Bim. In conclusion, our results demonstrate that the nephroprotective effects of PGE1 against apoptosis of proximal renal tubule in DKD rats via suppressing JNK-related Bim signaling pathway.