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

Abstract Hyperglycemia causes mitochondrial damage renal tubular cells, which contribute to the progression of diabetic kidney disease. However, the metabolic aberration of renal tubular cells in an hyperglycemic milieu has not been fully elucidated. In this study, human proximal renal tubular cell line (HK-2 cell) are incubated in glucose and mannitol at 5 mM or 25 mM. Cellular metabolome was determined by capillary electrophoresis time of flight mass spectrometer (CE-TOF/MS) and capillary electrophoresis-triple quadrupole mass spectrometry (CE-QqQMS). A total of 116 metabolites were quantified. Principal component analysis (PCA) revealed excellent clustering of metabolomic changes for different treatment conditions, and exposure to glucose at 5 and 25 mM lead to distinct metabolomic profiles as compared to samples treated with serum-free medium or mannitol as osmotic control. Hierarchical clustering analysis showed a number of characteristic changes in metabolic profile following exposure to 5 mM or 25 mM glucose. Notably, lactate-to-pyruvate ratio was significantly increased, while cellular levels of citric acid, α-ketoglutaric acid (i.e. 2-oxoglutaric acid), and fumaric acid were significantly reduced after exposure to glucose at 25 mM but not 5 mM. Moreover, cellular levels of reduced glutathione and total glutathione were significantly decreased, and S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) ratio was significantly increased after exposure to glucose 25 mM but not 5 mM. We conclude that in response to high glucose, HK-2 cells characteristic metabolomic changes, including increase in lactate-to-pyruvate ratio, reduction in Krebs cycle metabolites, reduction in glutathione antioxidant activity, and increase in cellular methylation potential. Our results may shed light on the pathogenesis of diabetic kidney disease, but the expression of glucose metabolism-related protein and enzyme activity in HK-2 cells after hyperglycemia condition need to be confirmed by further studies.

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LncRNA NEAT1 is involved in the protective effect of Klotho on renal tubular epithelial cells in diabetic kidney disease

10.26226/morressier.5d9b6233ea541d6ca849422a ◽

2019 ◽

Author(s):

Yan-Lin YANG

Keyword(s):

Kidney Disease ◽

Epithelial Cells ◽

Protective Effect ◽

Diabetic Kidney Disease ◽

Tubular Epithelial Cells ◽

Renal Tubular Epithelial Cells ◽

Diabetic Kidney ◽

Renal Tubular ◽

Lncrna Neat1

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METTL14-regulated PI3K/Akt signaling pathway via PTEN affects HDAC5-mediated epithelial–mesenchymal transition of renal tubular cells in diabetic kidney disease

Cell Death and Disease ◽

10.1038/s41419-020-03312-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Zhaoxia Xu ◽

Keqi Jia ◽

Hui Wang ◽

Feng Gao ◽

Song Zhao ◽

...

Keyword(s):

Kidney Disease ◽

High Glucose ◽

Diabetic Kidney Disease ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Renal Tubular ◽

Hk2 Cells ◽

Tgf Β1

AbstractHistone deacetylase 5 (HDAC5) belongs to class II HDAC subfamily and is reported to be increased in the kidneys of diabetic patients and animals. However, little is known about its function and the exact mechanism in diabetic kidney disease (DKD). Here, we found that HDAC5 was located in renal glomeruli and tubular cells, and significantly upregulated in diabetic mice and UUO mice, especially in renal tubular cells and interstitium. Knockdown of HDAC5 ameliorated high glucose-induced epithelial–mesenchymal transition (EMT) of HK2 cells, indicated in the increased E-cadherin and decreased α-SMA, via the downregulation of TGF-β1. Furthermore, HDAC5 expression was regulated by PI3K/Akt signaling pathway and inhibition of PI3K/Akt pathway by LY294002 treatment or Akt phosphorylation mutation reduced HDAC5 and TGF-β1 expression in vitro high glucose-cultured HK2 cells. Again, high glucose stimulation downregulated total m6A RNA methylation level of HK2 cells. Then, m6A demethylase inhibitor MA2 treatment decreased Akt phosphorylation, HDAC5, and TGF-β1 expression in high glucose-cultured HK2 cells. In addition, m6A modification-associated methylase METTL3 and METTL14 were decreased by high glucose at the levels of mRNA and protein. METTL14 not METTL3 overexpression led to PI3K/Akt pathway inactivation in high glucose-treated HK2 cells by enhancing PTEN, followed by HDAC5 and TGF-β1 expression downregulation. Finally, in vivo HDACs inhibitor TSA treatment alleviated extracellular matrix accumulation in kidneys of diabetic mice, accompanied with HDAC5, TGF-β1, and α-SMA expression downregulation. These above data suggest that METTL14-regulated PI3K/Akt signaling pathway via PTEN affected HDAC5-mediated EMT of renal tubular cells in diabetic kidney disease.

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Sitagliptin Ameliorates Renal Tubular Injury in Diabetic Kidney Disease via STAT3-Dependent Mitochondrial Homeostasis Through SDF-1α/CXCR4 Pathway

SSRN Electronic Journal ◽

10.2139/ssrn.3495589 ◽

2019 ◽

Author(s):

Qunzi Zhang ◽

Li He ◽

Feng Liu ◽

Jian Guan ◽

Yang Dong ◽

...

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Tubular Injury ◽

Diabetic Kidney ◽

Mitochondrial Homeostasis ◽

Renal Tubular

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Dapagliflozin Ameliorates Diabetic Kidney Disease via Upregulating Crry and Alleviating Complement Over-activation in db/db Mice

Frontiers in Pharmacology ◽

10.3389/fphar.2021.729334 ◽

2021 ◽

Vol 12 ◽

Author(s):

Dong-Yuan Chang ◽

Xiao-Qian Li ◽

Min Chen ◽

Ming-Hui Zhao

Keyword(s):

Kidney Disease ◽

Protective Effect ◽

High Glucose ◽

Diabetic Kidney Disease ◽

Membrane Attack Complex ◽

Sglt2 Inhibitors ◽

Tubulointerstitial Injury ◽

Diabetic Kidney ◽

Proximal Tubular Epithelial Cells ◽

Complement Regulator

Sodium-glucose cotransporter 2(SGLT2) inhibitors show prominent renal protective effect in diabetic kidney disease (DKD), anti-inflammatory effect being one of its key mechanisms. Over-activation of the complement system, a crucial part of innate immunity, plays an important role in DKD. We aimed to investigate the effect of SGLT2 inhibitors on alleviating complement over-activation in DKD. Db/db mice were randomly divided into two groups, with 7 mice in each group treated with dapagliflozin and vehicle respectively, and 7 mice in m/m mice group. Laboratory and renal pathological parameters were evaluated. Mouse proximal tubular epithelial cells (MPTECs) were cultured and treated with high glucose. Dapagliflozin and dimethyloxallyl glycine (DMOG) were added as conditional treatment. Dapagliflozin-treated db/db mice showed significantly lower urinary albumin than vehicle-treated ones. Besides typical glomerular and tubulointerstitial injury, both C3b and membrane attack complex (MAC) depositions were significantly attenuated in dapagliflozin-treated db/db mice. The expression of complement receptor type 1-related protein y (Crry), a key complement regulator which inhibits complement over-activation, was significantly upregulated by dapagliflozin. Dapagliflozin-mediated Crry upregulation was associated with inhibition of HIF-1α accumulation under high glucose. When HIF-1α expression was stabilized by DMOG, the protective effect of dapagliflozin via upregulating Crry was blocked. In conclusion, dapagliflozin could attenuate complement over-activation in diabetic mice via upregulating Crry, which is associated with the suppression of HIF-1α accumulation in MPTECs.

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20(S)-Ginsenoside Rg3 Protects Kidney from Diabetic Kidney Disease via Renal Inflammation Depression in Diabetic Rats

Journal of Diabetes Research ◽

10.1155/2020/7152176 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Tong Zhou ◽

Lin Sun ◽

Shuo Yang ◽

You Lv ◽

Yue Cao ◽

...

Keyword(s):

Treatment Group ◽

Kidney Disease ◽

Cell Apoptosis ◽

Diabetic Kidney Disease ◽

Diabetic Rats ◽

Diabetic Group ◽

Renal Tubular Cell ◽

Ginsenoside Rg3 ◽

Diabetic Kidney ◽

Renal Tubular

20(S)-Ginsenoside Rg3 (20(S)-Rg3) has been shown to induce apoptosis by interfering with several signaling pathways. Furthermore, it has been reported to have anticancer and antidiabetic effects. In order to detect the protective effect of 20(S)-Rg3 on diabetic kidney disease (DKD), diabetic rat models which were established by administering high-sugar, high-fat diet combined with intraperitoneal injection of streptozotocin (STZ), and age-matched wild-type (WT) rat were given 20(S)-Rg3 for 12 weeks, with three groups: control group (normal adult rats with saline), diabetic group (diabetic rats with saline), and 20(S)-Rg3 treatment group (diabetic rats with 20(S)-Rg3 (10 mg/kg body weight/day)). The biochemical indicators and the changes in glomerular basement membrane and mesangial matrix were detected. TUNEL staining was used to detect glomerular and renal tubular cell apoptosis. Immunohistochemical staining was used to detect the expression of fibrosis factors and inflammation factors in rat kidney tissues. Through periodic acid-Schiff staining, we observed that the change in renal histology was improved and renal tubular epithelial cell apoptosis decreased significantly by treatment with 20(S)-Rg3. Plus, the urine protein decreased in the rats with the 20(S)-Rg3 treatment. Fasting blood glucose, creatinine, total cholesterol, and triglyceride levels in the 20(S)-Rg3 treatment group were all lower than those in the diabetic group. Mechanistically, 20(S)-Rg3 dramatically downregulated the expression of TGF-β1, NF-κB65, and TNF-α in the kidney. These resulted in a significant prevention of renal damage from the inflammation. The results of the current study suggest that 20(S)-Rg3 could potentially be used as a novel treatment against DKD.

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