Fucoidan from Laminaria japonica Inhibits Expression of GLUT9 and URAT1 via PI3K/Akt, JNK and NF-κB Pathways in Uric Acid-Exposed HK-2 Cells

This work aimed to investigate the effect of fucoidan (FPS) on urate transporters induced by uric acid (UA). The results showed that UA stimulated the expression of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) in HK-2 cells, and FPS could reverse the effect. Moreover, UA could activate NF-κB, JNK and PI3K/Akt pathways, but both pathway inhibitors and FPS inhibited the UA-induced activation of these three pathways. These data suggested that FPS effectively inhibited the expression induction of reabsorption transporters URAT1 and GLUT9 by UA, through repressing the activation of NF-κB, JNK and PI3K/Akt signal pathways in HK-2 cells. The in vitro research findings support the in vivo results that FPS reduces serum uric acid content in hyperuricemia mice and rats through inhibiting the expression of URAT1 and GLUT9 in renal tubular epithelial cells. This study provides a theoretical basis for the application of FPS in the treatment of hyperuricemia.

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Epithelial—mesenchymal transformation of renal tubular epithelial cells in vitro and in vivo

Nephrology Dialysis Transplantation ◽

10.1093/ndt/15.suppl_6.44 ◽

2000 ◽

Vol 15 (suppl_6) ◽

pp. 44-46 ◽

Cited By ~ 37

Author(s):

H. Okada ◽

T. Inoue ◽

H. Suzuki ◽

F. Strutz ◽

E. G. Neilson

Keyword(s):

Epithelial Cells ◽

Tubular Epithelial Cells ◽

Renal Tubular Epithelial Cells ◽

Renal Tubular ◽

Mesenchymal Transformation

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Effect of Huai Qi Huang on Epithelial-Mesenchymal Transition of Renal Tubular Epithelial Cells through miR-200a

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/8612190 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Jinyun Pu ◽

Yu Zhang ◽

Jianhua Zhou

Keyword(s):

Epithelial Cells ◽

Molecular Mechanism ◽

Renal Fibrosis ◽

Epithelial Mesenchymal Transition ◽

Tubular Epithelial Cells ◽

Renal Tubular Epithelial Cells ◽

Mesenchymal Transition ◽

Renal Tubular

Epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells is a vital mechanism of renal fibrosis. Mounting evidence suggests that miR-200a expression decreases in tubular epithelial cells in unilateral ureteral obstruction (UUO) rats. Moreover, it has been demonstrated that Huai Qi Huang (HQH) can ameliorate tubulointerstitial damage in adriamycin nephrosis and delay kidney dysfunction in primary glomerular disease. However, the effect of HQH on EMT of tubular epithelial cells in UUO rats and its molecular mechanism is unclear. In order to explore the effect of HQH on EMT and its molecular mechanism in renal fibrosis,in vitroandin vivoexperiments were performed in our study. Our results showed that HQH increased miR-200a expression in UUO rats and in TGF-β1 stimulated NRK-52E cells. Meanwhile, HQH decreased ZEB1 and ZEB2 (the transcriptional repressors of E-cadherin),α-SMA expression in renal tubular epithelial cellsin vitroandin vivo. Furthermore, we found that HQH protected kidney from fibrosis in UUO rats. The results demonstrated that HQH regulated miR-200a/ZEBs pathway and inhibited EMT process, which may be a mechanism of protecting effect on tubular cells in renal fibrosis.

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Uric acid increases fibronectin synthesis through upregulation of lysyl oxidase expression in rat renal tubular epithelial cells

AJP Renal Physiology ◽

10.1152/ajprenal.00053.2010 ◽

2010 ◽

Vol 299 (2) ◽

pp. F336-F346 ◽

Cited By ~ 29

Author(s):

Zhou Yang ◽

Wang Xiaohua ◽

Jiang Lei ◽

Tan Ruoyun ◽

Xiong Mingxia ◽

...

Keyword(s):

Uric Acid ◽

Epithelial Cells ◽

Renal Disease ◽

Lysyl Oxidase ◽

Dependent Manner ◽

Tubular Epithelial Cells ◽

Fibronectin Expression ◽

Renal Tubular ◽

Interfering Rna

Urate is produced as the major end product of purine metabolism. In the last decade, the incidence of hyperuricemia increased markedly, and similar trends in the epidemiology of metabolic syndrome have been observed. Hyperuricemia is associated with renal disease, and recent studies have reported that mild hyperuricemia results in hypertension, intrarenal vascular disease, and renal injury. This has led to the hypothesis that uric acid may contribute to renal fibrosis and progressive renal disease. Our purpose was to investigate the relationship between uric acid and renal tubular injury. We applied the method of intraperitoneal injection of uric acid to generate the hyperuricemic mouse model. Compared with the saline injection group, the expression of lysyl oxidase (LOX) and fibronectin in kidneys was increased significantly in hyperuricemic groups. In vitro, uric acid significantly induced NRK-52E cells to express the ECM marker fibronectin, as well as LOX, which plays a pivotal role in ECM maturation, in a time- and dose-dependent manner. Upregulation of the urate transporter URAT1, which is located in the apical membrane of proximal tubules, sensitized the uric acid-induced fibronectin and LOX induction, while both knocking down URAT1 expression in tubular epithelial cells by RNA interference and inhibiting URAT1 function pharmacologically attenuated LOX and fibronectin expression. Furthermore, knockdown of LOX expression by a small interfering RNA strategy led to a decrease in fibronectin abundance induced by uric acid treatment. In addition, evidence of a uric acid-induced activation of the NF-κB signaling cascade was observed. Our findings highlight a need for carefully reevaluating our previous view on the pathological roles of hyperuricemia in the kidney and nephropathy induced by uric acid in clinical practice.

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SOX9 promotes stress-responsive transcription of VGF nerve growth factor inducible gene in renal tubular epithelial cells

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015110 ◽

2020 ◽

Vol 295 (48) ◽

pp. 16328-16341

Author(s):

Ji Young Kim ◽

Yuntao Bai ◽

Laura A. Jayne ◽

Ferdos Abdulkader ◽

Megha Gandhi ◽

...

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Epithelial Cells ◽

Tubular Epithelial Cells ◽

Renal Tubular Epithelial Cells ◽

Gene Ablation ◽

Renal Tubular ◽

Inducible Gene

Acute kidney injury (AKI) is a common clinical condition associated with diverse etiologies and abrupt loss of renal function. In patients with sepsis, rhabdomyolysis, cancer, and cardiovascular disorders, the underlying disease or associated therapeutic interventions can cause hypoxia, cytotoxicity, and inflammatory insults to renal tubular epithelial cells (RTECs), resulting in the onset of AKI. To uncover stress-responsive disease-modifying genes, here we have carried out renal transcriptome profiling in three distinct murine models of AKI. We find that Vgf nerve growth factor inducible gene up-regulation is a common transcriptional stress response in RTECs to ischemia-, cisplatin-, and rhabdomyolysis-associated renal injury. The Vgf gene encodes a secretory peptide precursor protein that has critical neuroendocrine functions; however, its role in the kidneys remains unknown. Our functional studies show that RTEC-specific Vgf gene ablation exacerbates ischemia-, cisplatin-, and rhabdomyolysis-associated AKI in vivo and cisplatin-induced RTEC cell death in vitro. Importantly, aggravation of cisplatin-induced renal injury caused by Vgf gene ablation is partly reversed by TLQP-21, a Vgf-derived peptide. Finally, in vitro and in vivo mechanistic studies showed that injury-induced Vgf up-regulation in RTECs is driven by the transcriptional regulator Sox9. These findings reveal a crucial downstream target of the Sox9-directed transcriptional program and identify Vgf as a stress-responsive protective gene in kidney tubular epithelial cells.

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Protective Mechanism of Qi-Dan-Dihuang Decoction in Diabetic Kidney Disease Based on Network pharmacology

10.21203/rs.3.rs-1010937/v1 ◽

2021 ◽

Author(s):

Liuyan Kuang ◽

Yanting You ◽

Jieying Qi ◽

Xinghong Zhou ◽

Jieyu Chen ◽

...

Keyword(s):

Diabetic Kidney Disease ◽

Kegg Pathway ◽

Network Pharmacology ◽

Tubular Epithelial Cells ◽

Renal Tubular Epithelial Cells ◽

Protein Expressions ◽

Mtor Protein ◽

Renal Tubular

Abstract Background: Qi-Dan-Dihuang Decoction (QDD) has been used for treating diabetic kidney disease (DKD), but the mechanisms are poorly understood. The aim of this study is to reveal the therapeutic effects and the mechanism of QDD in ameliorating DKD by network pharmacology, in vivo, and in vitro studies.Methods: The effect of QDD on body weight, fast blood glucose, oral glucose tolerance test (OGTT), 24 h urinary protein (24hU-Pro), serum creatinine (Scr), blood urea nitrogen (BUN), and pathological evaluation in kidney were investigated in vivo using C57BLKS/J db/db mice. The main active compounds of QDD, compound-disease interaction targets, and related processes and pathways were discerned by network pharmacology analysis through Chinese Medicine Systems Pharmacology Database (TCMSP) and TCM Database@Taiwan. The protein-protein interaction (PPI) network were established through STRING database. GO and KEGG pathway were used for analysis processes and pathways. Then Western blot was used to verified the predicted results. Finally, cell viability, wound healing and mainly pathway protein expression were detected in vitro using renal tubular epithelial cells HK-2 and NRK-52E cells.Results: Although QDD treatment showed no significant difference in FBG and AUC of OGTT, but had significant reduction in Scr level in C57BLKS/J db/db mice. Histopathologic results showed that QDD ameliorated the expansion of mesangial area, thickened membranes of Bowman’s capsules and basement membrane of glomerular capillaries, renal tubular epithelial cells vacuolar degeneration and reversed the glomerular and tubulointerstitial in C57BLKS/J db/db mice. For network pharmacology analysis of QDD, 143 active compounds related to 274 possible targets in QDD obtained and 117 compound-disease interaction targets were screened out combining with Genecards database. 18 key targets was excavated through network topological analysis. GO and KEGG pathway enrichment analysis showed that compound-disease interaction targets were significantly enriched in processes and pathways that are closely related to DKD. Western blot results showed that QDD significantly attenuated EMT-related proteins, p-NF-κb, IL-1β, IL-18, p-p38MAPK/p38MAPK, p-AKT/AKT, and p-mTOR/ mTOR protein expressions. Treatment with QDD could alleviate cell viability damaged, EMT process, p-NF-κb, IL-1β, IL-18, p-p38MAPK/p38MAPK, p-AKT/AKT and p-mTOR/ mTOR protein expressions by high D-gulcose.Conclusions: This study provides convincing evidence suggest that QDD protects renal fibrosis of DKD, by regulating EMT in RTECs and inflammatory response through p38MAPK and AKT/mTOR signaling pathways.

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Active Components from Lagotis Brachystachya Maintain Uric Acid Homeostasis by Inhibiting Renal TLR4-NLRP3 Signaling in Hyperuricemic Mice

10.21203/rs.3.rs-283474/v1 ◽

2021 ◽

Author(s):

Ji-Xiao Zhu ◽

Hai-Yan Yang ◽

Wei-Qiong Hu ◽

Jie Cheng ◽

Yang Liu ◽

...

Keyword(s):

Uric Acid ◽

Glucose Transporter ◽

Organic Anion ◽

Underlying Mechanism ◽

Organic Anion Transporter ◽

Active Components ◽

Inflammatory Signaling ◽

Anion Transporter ◽

Glucose Transporter 9

Abstract Lagotis brachystachya Maxim is an herb widely used in traditional Tibet medicine. Our previous study indicated that total extracts from Lagotis brachystachya could lower uric acid levels. This study aimed to further elucidate the active components (luteolin, luteoloside and apigenin) isolated from Lagotis brachystachya and the underlying mechanism in vitro and vivo. The results showed that treatment with luteolin and luteoloside reversed the reduction of organic anion transporter 1 (OAT1) levels, while apigenin attenuated the elevation of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) levels in uric acid-treated HK-2 cells, which were consistent with the finding in the kidney of potassium oxonate (PO)-induced mice. On the other hand, hepatic xanthine oxidase activity was inhibited by the components. In addition, all of these active components improved the morphology of the kidney in hyperuricemic mice. Moreover, molecular docking showed that luteolin, luteoloside and apigenin could bind TLR4 and NLRP3. Consistently, western blot showed that the components inhibited TLR4/MyD88/NLRP3 signaling. In conclusion, these results indicated that luteolin, luteoloside and apigenin could attenuate hyperuricemia by decreasing the production and increasing the excretion of uric acid, which were mediated by the inhibition of inflammatory signaling pathways.

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Aldosterone Induces the Proliferation of Renal Tubular Epithelial Cells In Vivo but Not In Vitro

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1155/2021/9943848 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Juan Hao ◽

Lingjin Liu ◽

Ziqian Liu ◽

Gege Chen ◽

Yunzhao Xiong ◽

...

Keyword(s):

Flow Cytometry ◽

Cell Proliferation ◽

Epithelial Cells ◽

Mtt Assay ◽

Tubular Epithelial Cells ◽

Renal Tubular Epithelial Cells ◽

Renal Tubular ◽

Hk2 Cells

Objective. To investigate the proliferation effect of aldosterone on renal tubular epithelial cells in vivo and in vitro. Methods. Thirty-two male C57BL/6J mice (20–22 g) were divided randomly into four groups: sham, unilateral nephrectomy (UN), unilateral nephrectomy plus aldosterone infusion (UA), and UA plus eplerenone (UAE). The kidneys were removed 6 weeks after treatment. Expression of proliferating cell nuclear antigen (PCNA) was detected by immunohistochemistry and western blotting. Human kidney proximal tubular epithelial (HK2) and mouse distal convoluted tubule (mDCT) cell lines were stimulated by aldosterone (0, 10−9, 10−8, 10−7, and 10−6 mol/L) in vitro. Cells were collected after 3, 6, 12, 24, 36, and 48 h, and proliferation of each group detected by western blotting, flow cytometry, live imaging, and the MTT assay. In addition, mDCT cells were costimulated with a medium containing a final concentration of 161 mmol/L Na+ and different concentrations of aldosterone, and the number of cells and cellular DNA content was measured by the MTT assay and flow cytometry. Results. Aldosterone could induce a significant increase in the number of PCNA-positive cells in mouse kidneys accompanied by increased deposition of collagen fibers. Eplerenone could inhibit aldosterone-induced cell proliferation and collagen deposition. HK2 cells and mDCT cells administered different concentrations, and different times of aldosterone stimulation failed to cause cell proliferation, and costimulation of aldosterone and salt did not cause proliferation changes in mDCT cells. Conclusions. Aldosterone perfusion can induce proliferation of mouse kidney cells in vivo, and eplerenone can inhibit this change, but aldosterone stimulates HK2 cells and mDCT in vitro without causing their proliferation.

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