High Glucose Enhances oxLDL-Induced Apoptosis in Human Renal Proximal Tubular Epithelial Cells Largely via Inducing Lectin-Like ox-LDL Receptor-1

Zhou, Xiaorong; Liu, Ruihong; Duan, Shao‐Bin; Huang, Guxiang; Ye, Yun; Kong, Ying

doi:10.1159/000444934

Cited by 5 publications

(3 citation statements)

References 21 publications

(38 reference statements)

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“…Increasing studies have suggested that an increase in the activity of p38 MAPK and ERK1/2 contributes to the etiopathogenesis of DN ( 36 , 37 ). Numerous studies have suggested that GSPEs may protect the kidney by suppressing p38 MAPK and ERK1/2 phosphorylation ( 38 , 39 ).…”

Section: Discussionmentioning

confidence: 99%

Anthocyanins inhibit high glucose-induced renal tubular cell apoptosis caused by oxidative stress in db/db mice

Wei

Zhang

et al. 2018

Int J Mol Med

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Oxidative stress is an important contributory factor resulting the development of kidney injury in patients with diabetes. Numerous in vitro and in vivo studies have suggested that anthocyanins, natural phenols commonly existing in numerous fruits and vegetables, exhibit important anti-oxidative, anti-inflammatory and antihyperlipidemic effects; however, their effects and underlying mechanisms on diabetic nephropathy (DN) have not yet been fully determined. In the present study, the regulation of apoptosis metabolism and antioxidative effects exhibited by anthocyanins [grape seed procyanidin (GSPE) and cyanidin-3-O-β-glucoside chloride (C3G)] were investigated, and the molecular mechanism underlying this process was investigated in vivo and in vitro. GSPE administration was revealed to suppress renal cell apoptosis, as well as suppress the expression of Bcl-2 in diabetic mouse kidneys. Furthermore, GSPE administration was demonstrated to suppress the expression of thioredoxin interacting protein (TXNIP), in addition to enhancing p38 mitogen-activation protein kinase (MAPK) and extracellular signal-regulated kinase 1/2 (ERK1/2) oxidase activity in diabetic mouse kidneys. In vitro experiments using HK-2 cells revealed that C3G suppressed the generation of HG-mediated reactive oxygen species, cellular apoptosis, the expression of cleaved caspase-3 and the Bax/Bcl-2 ratio; and enhanced the expression of cytochrome c released from mitochondria. Furthermore, treatment with C3G was revealed to suppress the expression of TXNIP, in addition to the phosphorylation of p38 MAPK and ERK1/2 oxidase activity in HK-2 cells under HG conditions. In addition, treatment with C3G was revealed to attenuate the HG-induced suppression of the biological activity of thioredoxin, and to enhance the expression of thioredoxin 2 in HK-2 cells under HG conditions. In conclusion, the present study demonstrated that anthocyanins may exhibit protective effects against HG-induced renal injury in DN via antioxidant activity.

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Section: Discussionmentioning

confidence: 99%

Anthocyanins inhibit high glucose-induced renal tubular cell apoptosis caused by oxidative stress in db/db mice

Wei

Zhang

et al. 2018

Int J Mol Med

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“…Uptake of cholesterol is increased by tubular epithelial cells in DN with downregulation of cholesterol efflux genes, e.g., ABCA1, ABCG and upregulation of lipoprotein receptors, e.g., LOX-1, CD36 [18,21,22], and aggravates oxidative stress in tubular epithelial cells. In addition, oxidized LDL could directly induce inflammation, apoptosis and fibrosis on tubular epithelial cells [23][24][25]. And oxidized LDL was reported able to predict eGFR deterioration in proteinuric diabetic kidney disease [23].…”

Section: Discussionmentioning

confidence: 99%

Urinary RBP as an Independent Predictor of Renal Outcome in Diabetic Nephropathy

et al. 2022

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Background. Renal tubular impairment is prevalent in diabetic nephropathy (DN) and the histological severity predicted renal outcome. Biomarkers of tubular injury also increased in the urine of DN patients. The retrospective study aimed to assess the prognostic value of clinically widely applied urinary tubular injury markers, retinol-binding protein (RBP), β2-microglobulin (β2-MG) and N-acetyl-β-D-glucosaminidase (NAG) in DN. Method. A total of 305 patients with biopsy-proven DN were enrolled. The baseline urine total protein and components including albumin, IgG, RBP, β2-MG and NAG were retrieved from medical records. The primary outcome was end stage renal disease (ESRD). Cox proportional hazard analysis and restricted cubic splines were performed to evaluate the association of parameters with ESRD. Nomograms were constructed and concordance index (C-index) was used to measure the prediction ability. Result. The levels of urinary RBP, β2-MG and NAG were positively correlated with the severity of interstitial fibrosis and tubular atrophy (IFTA). Positive correlations were also observed among β2-MG, NAG and mesangial expansion. Urinary RBP was not correlated with any glomerular lesions. Urinary RBP, β2-MG and NAG were risk factors for ESRD in hazard analysis with adjustment for age, gender and body mass index (BMI). The hazard ratios increased with the increment of baseline levels. In the multivariate Cox model including serum creatinine (SCr), total urinary protein, urinary albumin, urinary IgG and the tubular injury biomarkers, urinary RBP (with every g/mol.Cr increase: HR 1.06, 95% CI 1.03-1.10, p =0.001) remained as an independent risk factor for ESRD in DN patients. Patients were divided by the medium value of urinary RBP into the low RBP and high RBP groups. Survival analysis showed that significantly more patients in the high RBP progressed to ESRD compared to those in the low RBP group (p =0.02) when urinary total protein was less than 3.5 g/g. The C-index of the nomogram incorporating age, gender, BMI, SCr and total urine protein was 0.757. The value increased to 0.777 after adding urinary RBP to the model. Conclusions. Urinary RBP excretion was only correlated with the severity of IFTA and independently predicted ESRD in DN patients.

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“…Recently, there has been increasing interest in the role of LOX-1 in the progression of renal diseases. A previous study has reported that high glucose levels can induce the expression of LOX-1 at the gene promoter/transcription level via a p38 MAPK-dependent mechanism, leading to Ox-LDL-induced apoptosis in renal tubular epithelial cells (27). It has also been reported that LOX-1 and NADPH oxidase are upregulated in human renal proximal tubular epithelial cells induced with angiotensin II (Ang II), and that the activation of the MAPK pathway occurs downstream of the Ang II/ROS/LOX-1 cascade (28).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of probucol on Ox-LDL-induced epithelial-mesenchymal transition in human renal proximal tubular epithelial cells via LOX‑1/ROS/MAPK signaling

et al. 2017

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Oxidized low-density lipoprotein (Ox-LDL), as a strong oxidant, results in renal injury through multiple mechanisms. The aim of the present study was to determine the injury effects of Ox‑LDL and the potential protective effects of the antioxidant reagent probucol on epithelial‑mesenchymal transition (EMT) in human renal proximal tubular epithelial cells (HK‑2) and to further explore the role and interrelation of lectin‑like oxidized low‑density lipoprotein receptor‑1 (LOX‑1), reactive oxygen species (ROS) and mitogen‑activated protein kinase (MAPK) pathway. In the present study, concentrations of 0‑100 µg/ml Ox‑LDL were used to induce HK‑2 cell EMT. Then, probucol (20 µmol/l) and the LOX‑1 inhibitor, polyinosinic acid (250 µg/ml), were also used to pretreat HK‑2 cells. Intracellular ROS activity was evaluated using the specific probe 2',7'‑dichlorodihydrofluorescein diacetate (DCFH‑DA). Concentration of nitric oxide (NO) was determined using a biochemical colorimetric method. Expression of E‑cadherin, α‑smooth muscle actin (SMA), LOX‑1, NADPH oxidase 4 (NOX4), cytochrome b‑245 α chain (p22phox), extracellular signal‑regulated kinase (ERK), and p38 MAPK protein levels were examined by western blotting. The results revealed that Ox‑LDL induced the expression of LOX‑1 and α‑SMA and reduced the expression of E‑cadherin in a dose‑dependent manner, and these effects were inhibited by polyinosinic acid or probucol pretreatment. Stimulation with 50 µg/ml Ox‑LDL induced the expression of NOX4 and p22phox and increased intracellular ROS activity, but NO production in the cell supernatants was not affected. The Ox‑LDL‑mediated increases in Nox4 and p22phox expression and in ROS activity were inhibited by probucol pretreatment. Further investigations into the underlying molecular pathways demonstrated that ERK and p38 MAPK were activated by Ox‑LDL stimulation and then inhibited by probucol pretreatment. The findings of the present study therefore suggest that Ox‑LDL induced EMT in HK‑2 cells, the mechanism of which may be associated with LOX‑1‑related oxidative stress via the ERK and p38 MAPK pathways. Notably, pretreatment with probucol inhibited the Ox‑LDL‑induced oxidative stress by reducing the expression of LOX‑1, and blocked the progression of EMT.

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High Glucose Enhances oxLDL-Induced Apoptosis in Human Renal Proximal Tubular Epithelial Cells Largely via Inducing Lectin-Like ox-LDL Receptor-1

Cited by 5 publications

References 21 publications

Anthocyanins inhibit high glucose-induced renal tubular cell apoptosis caused by oxidative stress in db/db mice

Anthocyanins inhibit high glucose-induced renal tubular cell apoptosis caused by oxidative stress in db/db mice

Urinary RBP as an Independent Predictor of Renal Outcome in Diabetic Nephropathy

Protective effects of probucol on Ox-LDL-induced epithelial-mesenchymal transition in human renal proximal tubular epithelial cells via LOX‑1/ROS/MAPK signaling

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