scholarly journals Ethyl Pyruvate Directly Attenuates Active Secretion of HMGB1 in Proximal Tubular Cells via Induction of Heme Oxygenase-1

2019 ◽  
Vol 8 (5) ◽  
pp. 629 ◽  
Author(s):  
Min Suk Seo ◽  
Hye Jung Kim ◽  
Hwajin Kim ◽  
Sang Won Park
Keyword(s):  
Heme Oxygenase ◽  
Ethyl Pyruvate ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Tubular Damage ◽  
High Morbidity ◽  
Proximal Tubular Cells ◽  
Active Secretion ◽  
Tubular Cells ◽  
Proximal Tubular

Renal ischemia reperfusion (IR) is a main cause of acute kidney injury leading to high morbidity and mortality during postoperative periods. This study investigated whether ethyl pyruvate (EP) protects the kidney against renal IR injury. Male C57BL/6 mice were treated with vehicle or EP (40 mg/kg) 1 h before ischemia and the plasma creatinine (Cr) levels and tubular damage were evaluated after reperfusion. EP attenuated the IR-induced plasma Cr levels, renal inflammation and apoptotic cell death, but the effect of EP was abolished by pretreating Zinc protoporphyrin (ZnPP), a heme oxygenase (HO)-1 inhibitor. HO-1 is a stress-induced protein and protects the kidney against IR injury. EP increased significantly HO-1 expression in the proximal tubular cells in vivo and HK-2 cells in vitro. Inhibition of PI3K/Akt pathway and knockdown of Nrf2 blocked HO-1 induction by EP. High mobility group box 1 (HMGB1) secretion was assessed as an early mediator of IR injury; plasma HMGB1 were significantly elevated as early as 2 h to 24 h after reperfusion and these were attenuated by EP, but the effect of EP was abolished by ZnPP. EP also reduced HMGB1 secretion stimulated by TNF-α in HK-2 cells, and the inhibition of PI3K/Akt and knockdown of HO-1 blocked the effect of EP. Conclusively, EP inhibits the active secretion of HMGB1 from proximal tubular cells during IR injury by inducing HO-1 via activation of PI3K/Akt and Nrf2 pathway.

scholarly journals Sodium Glucose Co-Transporter 2 Inhibitor Ameliorates Autophagic Flux Impairment on Renal Proximal Tubular Cells in Obesity Mice

2020 ◽  
Vol 21 (11) ◽  
pp. 4054
Author(s):  
Kazuhiko Fukushima ◽  
Shinji Kitamura ◽  
Kenji Tsuji ◽  
Yizhen Sang ◽  
Jun Wada
Keyword(s):  
Renal Injury ◽  
Tubular Damage ◽  
Autophagic Flux ◽  
Protective Effects ◽  
Renal Protection ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular

Obesity is supposed to cause renal injury via autophagy deficiency. Recently, sodium glucose co-transporter 2 inhibitors (SGLT2i) were reported to protect renal injury. However, the mechanisms of SGLT2i for renal protection are unclear. Here, we investigated the effect of SGLT2i for autophagy in renal proximal tubular cells (PTCs) on obesity mice. We fed C57BL/6J mice with a normal diet (ND) or high-fat and -sugar diet (HFSD) for nine weeks, then administered SGLT2i, empagliflozin, or control compound for one week. Each group contained N = 5. The urinary N-acetyl-beta-d-glucosaminidase level in the HFSD group significantly increased compared to ND group. The tubular damage was suppressed in the SGLT2i–HFSD group. In electron microscopic analysis, multi lamellar bodies that increased in autophagy deficiency were increased in PTCs in the HFSD group but significantly suppressed in the SGLT2i group. The autophagosomes of damaged mitochondria in PTCs in the HFSD group frequently appeared in the SGLT2i group. p62 accumulations in PTCs were significantly increased in HFSD group but significantly suppressed by SGLT2i. In addition, the mammalian target of rapamycin was activated in the HFSD group but significantly suppressed in SGLT2i group. These data suggest that SGLT2i has renal protective effects against obesity via improving autophagy flux impairment in PTCs on a HFSD.

Regenerative and Proinflammatory Effects of Thrombin on Human Proximal Tubular Cells

2000 ◽  
Vol 11 (6) ◽  
pp. 1016-1025 ◽  
Author(s):  
GIUSEPPE GRANDALIANO ◽  
RAFFAELLA MONNO ◽  
ELENA RANIERI ◽  
LORETO GESUALDO ◽  
FRANCESCO P. SCHENA ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Dna Synthesis ◽  
Coagulation Cascade ◽  
Tubular Damage ◽  
Thymidine Uptake ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Gene And Protein Expression ◽  
Proximal Tubular

Abstract. Interstitial fibrin deposition is a common histologic feature of tubulointerstitial diseases, which suggests that the coagulation system is activated. Thrombin, generated during the activation of the coagulation cascade, is a powerful activating factor for different cell types. Although proximal tubular cells are potential targets for this coagulation factor, no information is available on the effect of thrombin on these cells. Thus, the expression of protease-activated receptor-1 (PAR-1), the main thrombin receptor, was investigated in human proximal tubular cells (hPTC)in vivoandin vitro. A diffuse expression of PAR-1 was observed by immunohistochemistry along the basolateral membrane of PTC in normal human kidney. This observation was confirmedin vitroin cultured hPTC. Because tubular damage and monocyte infiltration are two hallmarks of tubulointerstitial injury, the effect of thrombin on DNA synthesis and monocyte chemotactic peptide-1 (MCP-1) gene and protein expression was evaluated in cultured hPTC. Thrombin induced a significant and dose-dependent increase in thymidine uptake and a striking upregulation of MCP-1 mRNA expression and protein release into the supernatant. Although PAR-1 is a G protein-coupled receptor, its activation in hPTC, as in other cell systems, resulted in a transient increase in cellular levels of tyrosine-phosphorylated proteins. An increased level of tyrosine-phosphorylated c-src suggested the activation of this cytoplasmic tyrosine kinase in response to thrombin and its potential role in thrombin-induced protein-tyrosine phosphorylation. Interestingly, thrombin-induced DNA synthesis and MCP-1 gene expression were completely blocked by genistein, a specific tyrosine kinase inhibitor, but not by its inactive analogue daidzein, demonstrating a central role for tyrosine kinase activation in the thrombin effects on hPTC. Moreover, the specific src inhibitor PP1 abolished the thrombin effect on DNA synthesis. In conclusion, thrombin might represent a powerful regenerative and proinflammatory stimulus for hPTC in acute and chronic tubulointerstitial diseases.

scholarly journals The importance of urinary enzymes in diagnostic of tubular damage caused by proteinuria

2002 ◽  
Vol 21 (3) ◽  
pp. 287-290 ◽  
Author(s):  
Radmila Obrenovic ◽  
Dejan Petrovic ◽  
Nada Majkic-Singh ◽  
Mileta Poskurica ◽  
Biljana Stojimirovic
Keyword(s):  
Alkaline Phosphatase ◽  
Creatinine Clearance ◽  
Tubular Damage ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Sensitive Parameter ◽  
The Third ◽  
Glomerular Proteinuria ◽  
Proximal Tubular ◽  
Different Levels

Proteinuria causes damage to proximal tubular cells. To investigate the influence of different levels of glomerular proteinuria, we examined 50 patients (24 male and 26 female). Their creatinine clearance (Ccr) was higher than 50 mL/min (87,29"31,17 mL/min). According to the proteinuria range level patients were separated in three groups. The first group, with proteinuria less than 0,3 g/24h, included 19 persons (7 man and 12 woman), mean age 45,12"13,28 years and mean Ccr 94,27"34,70 mL/min. Proteinuria 0,3?3,0 g/24h is the second group characteristic. This group included 18 patients (8 male and 10 female) mean age 45,39"12,64 years, with mean 90,07"31,89 mL/min. Patients with proteinuria higher than 3,0 g/24h were members of third group. Mean age 50,08"13,73 years and mean Ccr 73,25"20,44 mL/min are caracteristics of 13 members (9 male and 4 female) of the third group. Enzymes alkaline phosphatase (AP), g-glutamil transpherase (gGT) and Nacetyl- b-D-glucosaminidase (b-NAG) were used as parameters of tubular damage. Gama-glutamil transpherase is more sensitive parameter of tubular damage then alkaline phosphatase. N-acetyl-b-D-glucosaminidase is the most sensitive parameter of tubular damage due to proteinuria.

Low-affinity transport of pyroglutamyl-histidine in renal brush-border membrane vesicles

1989 ◽  
Vol 257 (5) ◽  
pp. C971-C975 ◽  
Author(s):  
H. A. Skopicki ◽  
K. Fisher ◽  
D. Zikos ◽  
G. Flouret ◽  
D. R. Peterson
Keyword(s):  
Brush Border ◽  
Brush Border Membrane ◽  
Membrane Vesicles ◽  
Brush Border Membrane Vesicles ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Luminal Membrane ◽  
Renal Brush Border Membrane ◽  
Proximal Tubular ◽  
Renal Brush Border

These studies were performed to determine if a low-affinity carrier is present in the luminal membrane of proximal tubular cells for the transport of the dipeptide, pyroglutamyl-histidine (pGlu-His). We have previously described the existence of a specific, high-affinity, low-capacity [transport constant (Kt) = 9.3 X 10(-8) M, Vmax = 6.1 X 10(-12) mol.mg-1.min-1] carrier for pGlu-His in renal brush-border membrane vesicles. In the present study, we sought to demonstrate that multiple carriers exist for the transport of a single dipeptide by determining whether a low-affinity carrier also exists for the uptake of pGlu-His. Transport of pGlu-His into brush-border membrane vesicles was saturable over the concentration range of 10(-5)-10(-3) M, yielding a Kt of 6.3 X 10(-5) M and a Vmax of 2.2 X 10(-10) mol.mg-1.min-1. Uptake was inhibited by the dipeptides glycyl-proline, glycyl-sarcosine, and carnosine but not by the tripeptide pyroglutamyl-histidyl-prolinamide. We conclude that 1) pGlu-His is transported across the luminal membrane of the proximal tubule by multiple carriers and 2) the lower affinity carrier, unlike the higher affinity carrier, is nonspecific with respect to other dipeptides.

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