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

ABSTRACT: 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.

SUBMITTER: Guo C

PROVIDER: S-EPMC6289038 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Guo Congcong C Li Yun Y Zhang Rui R Zhang Yaqin Y Zhao Junyu J Yao Jinming J Sun Jie J Dong Jianjun J Liao Lin L

Frontiers in pharmacology 20181204

<b>Background:</b> 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. <b>Methods:</b> Twenty-eight male Wistar rats were allocated into four groups: sham-operated, uninephrectomy (unx), diabetes with uninephrectomy (DKD) and DKD treated with ...[more]

PMID: 30564128

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Project description:BackgroundDiabetic kidney disease (DKD) has mainly been considered as a glomerular disease. Our previous study showed that the progression of DKD was highly correlated with the dysfunction of renal proximal tubular cells. Fermented Cordyceps sinensis (CS), a substitute for natural CS, is a prominent herb widely used in China, and has exhibited excellent efficacy on DKD. However, the underlying mechanisms remain poorly understood.MethodsThe database analysis was used to identify the main therapeutic targets and pathways of CS involved in DKD treatment. Next, the protective effects of fermented CS on high glucose (HG, 30 mM) induced HK-2 cell injury was validated through cell proliferation and apoptosis assay, including CCK-8, EdU and TUNEL. Finally, quantitative real‑time PCR (qRT-PCR) and western blotting were used to verify key target genes.ResultsOur results revealed that 9 main targets (RELA, JNK1, PTEN, VEGFA, EGF, ERK2, CASP3, AKT1, MMP9) were recognized as key therapeutic targets with excellent binding affinity screened by database analysis and molecular docking. The biological processes were identified by Gene Ontology (GO) enrichment, which appeared mainly involved in the positive regulation of cell proliferation as well as the negative regulation of apoptosis. The verification experiments in vitro revealed that fermented CS significantly attenuated the HG-induced cytotoxicity and apoptosis, and promoted the proliferation of HK-2 cells. Moreover, fermented CS significantly downregulated the expressions of Bax, Caspase-3, VEGFA, P-AKT and P-ERK, and upregulated the expression of PTEN compared with that of HG group.ConclusionOur results demonstrate that the fermented CS has nephroprotective effects significantly, which functions via promoting proliferation and inhibiting apoptosis of renal proximal tubular cells, likely by targeting Caspase-3, Bax, VEGFA and PTEN. Furthermore, AKT and ERK signaling pathway may be the critical mechanisms underlying the efficacy of fermented CS in DKD treatment.

Project description:Diabetes mellitus (DM) causes ototoxicity by inducing oxidative stress, microangiopathy, and apoptosis in the cochlear sensory hair cells. The natural anti-oxidant pterostilbene (PTS) (trans-3,5-dimethoxy-4-hydroxystylbene) has been reported to relieve oxidative stress and apoptosis in DM, but its role in diabetic-induced ototoxicity is unclear. This study aimed to investigate the effects of dose-dependent PTS on the cochlear cells of streptozotocin (STZ)-induced diabetic rats. The study included 30 albino male Wistar rats that were randomized into five groups: non-diabetic control (Control), diabetic control (DM), and diabetic rats treated with intraperitoneal PTS at 10, 20, or 40 mg/kg/day during the four-week experimental period (DM + PTS10, DM + PTS20, and DM + PTS40). Distortion product otoacoustic emission (DPOAE) tests were performed at the beginning and end of the study. At the end of the experimental period, apoptosis in the rat cochlea was investigated using caspase-8, cytochrome-c, and terminal deoxyribonucleotidyl transferase-mediated dUTP-biotin end labeling (TUNEL). Quantitative real-time polymerase chain reaction was used to assess the mRNA expression levels of the following genes: CASP-3, BCL-associated X protein (BAX), and BCL-2. Body weight, blood glucose, serum insulin, and malondialdehyde (MDA) levels in the rat groups were evaluated. The mean DPOAE amplitude in the DM group was significantly lower than the means of the other groups (0.9-8 kHz; P < 0.001 for all). A dose-dependent increase of the mean DPOAE amplitudes was observed with PTS treatment (P < 0.05 for all). The Caspase-8 and Cytochrome-c protein expressions and the number of TUNEL-positive cells in the hair cells of the Corti organs of the DM rat group were significantly higher than those of the PTS treatment and control groups (DM > DM + PTS10 > DM + PTS20 > DM + PTS40 > Control; P < 0.05 for all). PTS treatment also reduced cell apoptosis in a dose-dependent manner by increasing the mRNA expression of the anti-apoptosis BCL2 gene and by decreasing the mRNA expressions of both the pro-apoptosis BAX gene and its effector CASP-3 and the ratio of BAX/BCL-2 in a dose-dependent manner (P < 0.05 compared to DM for all). PTS treatment significantly improved the metabolic parameters of the diabetic rats, such as body weight, blood glucose, serum insulin, and MDA levels, consistent with our other findings (P < 0.05 compared to DM for all). PTS decreased the cochlear damage caused by diabetes, as confirmed by DPOAE, biochemical, histopathological, immunohistochemical, and molecular findings. This study reports the first in vivo findings to suggest that PTS may be a protective therapeutic agent against diabetes-induced ototoxicity.

Dataset Information

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

Publications

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

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