scholarly journals Role of Calbindin-D28k in Diabetes-Associated Advanced Glycation End-Products-Induced Renal Proximal Tubule Cell Injury

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 660 ◽  
Author(s):  
Kuo-How Huang ◽  
Siao-Syun Guan ◽  
Wei-Han Lin ◽  
Cheng-Tien Wu ◽  
Meei-Ling Sheu ◽  
...  
Keyword(s):  
Er Stress ◽  
Proximal Tubule ◽  
Cell Injury ◽  
Renal Proximal Tubule ◽  
Proximal Tubule Cells ◽  
Glycation End Products ◽  
Calbindin D28k ◽  
Renal Proximal Tubule Cells ◽  
Emt Markers

Diabetes-associated advanced glycation end-products (AGEs) can increase extracellular matrix (ECM) expression and induce renal fibrosis. Calbindin-D28k, which plays a role in calcium reabsorption in renal distal convoluted tubules, is increased in a diabetic kidney. The role of calbindin-D28k in diabetic nephropathy still remains unclear. Here, calbindin-D28k protein expression was unexpectedly induced in the renal tubules of db/db diabetic mice. AGEs induced the calbindin-D28k expression in human renal proximal tubule cells (HK2), but not in mesangial cells. AGEs induced the expression of fibrotic molecules, ECM proteins, epithelial-mesenchymal transition (EMT) markers, and endoplasmic reticulum (ER) stress-related molecules in HK2 cells, which could be inhibited by a receptor for AGE (RAGE) neutralizing antibody. Calbindin-D28k knockdown by siRNA transfection reduced the cell viability and obviously enhanced the protein expressions of fibrotic factors, EMT markers, and ER stress-related molecules in AGEs-treated HK2 cells. Chemical chaperone 4-Phenylbutyric acid counteracted the AGEs-induced ER stress and ECM and EMT markers expressions. Calbindin-D28k siRNA in vivo delivery could enhance renal fibrosis in db/db diabetic mice. These findings suggest that inducible calbindin-D28k protects against AGEs/RAGE axis-induced ER stress-activated ECM induction and cell injury in renal proximal tubule cells.

ER stress contributes to renal proximal tubule injury by increasing SREBP-2-mediated lipid accumulation and apoptotic cell death

2012 ◽  
Vol 303 (2) ◽  
pp. F266-F278 ◽  
Author(s):  
Šárka Lhoták ◽  
Sudesh Sood ◽  
Elise Brimble ◽  
Rachel E. Carlisle ◽  
Stephen M. Colgan ◽  
...  
Keyword(s):  
Er Stress ◽  
Proximal Tubule ◽  
Lipid Accumulation ◽  
Cell Injury ◽  
Apoptotic Cell ◽  
Renal Proximal Tubule ◽  
Proximal Tubule Cell ◽  
Tubule Cell ◽  
Proximal Tubule Cells ◽  
Tubule Cells

Renal proximal tubule injury is induced by agents/conditions known to cause endoplasmic reticulum (ER) stress, including cyclosporine A (CsA), an immunosuppressant drug with nephrotoxic effects. However, the underlying mechanism by which ER stress contributes to proximal tubule cell injury is not well understood. In this study, we report lipid accumulation, sterol regulatory element-binding protein-2 (SREBP-2) expression, and ER stress in proximal tubules of kidneys from mice treated with the classic ER stressor tunicamycin (Tm) or in human renal biopsy specimens showing CsA-induced nephrotoxicity. Colocalization of ER stress markers [78-kDa glucose regulated protein (GRP78), CHOP] with SREBP-2 expression and lipid accumulation was prominent within the proximal tubule cells exposed to Tm or CsA. Prolonged ER stress resulted in increased apoptotic cell death of lipid-enriched proximal tubule cells with colocalization of GRP78, SREBP-2, and Ca2+-independent phospholipase A2 (iPLA2β), an SREBP-2 inducible gene with proapoptotic characteristics. In cultured HK-2 human proximal tubule cells, CsA- and Tm-induced ER stress caused lipid accumulation and SREBP-2 activation. Furthermore, overexpression of SREBP-2 or activation of endogenous SREBP-2 in HK-2 cells stimulated apoptosis. Inhibition of SREBP-2 activation with the site-1-serine protease inhibitor AEBSF prevented ER stress-induced lipid accumulation and apoptosis. Overexpression of the ER-resident chaperone GRP78 attenuated ER stress and inhibited CsA-induced SREBP-2 expression and lipid accumulation. In summary, our findings suggest that ER stress-induced SREBP-2 activation contributes to renal proximal tubule cell injury by dysregulating lipid homeostasis.

scholarly journals Role of proteoglycans and cytoskeleton in the effects of TGF-β1 on renal proximal tubule cells

1993 ◽  
Vol 43 (3) ◽  
pp. 575-584 ◽  
Author(s):  
H. David Humes ◽  
Takamichi Nakamura ◽  
Deborah A. Cieslinski ◽  
Diane Miller ◽  
Robert V. Emmons ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Renal Proximal Tubule ◽  
Proximal Tubule Cells ◽  
Tubule Cells ◽  
Renal Proximal Tubule Cells ◽  
Tgf Β1

scholarly journals Unique role of NADPH oxidase 5 in oxidative stress in human renal proximal tubule cells

Redox Biology ◽  
2014 ◽  
Vol 2 ◽  
pp. 570-579 ◽  
Author(s):  
Peiying Yu ◽  
Weixing Han ◽  
Van Anthony M. Villar ◽  
Yu Yang ◽  
Quansheng Lu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Proximal Tubule ◽  
Renal Proximal Tubule ◽  
Proximal Tubule Cells ◽  
Unique Role ◽  
Tubule Cells ◽  
Renal Proximal Tubule Cells ◽  
Nadph Oxidase 5

Effect of BSA-induced ER stress on SGLT protein expression levels and α-MG uptake in renal proximal tubule cells

2009 ◽  
Vol 296 (6) ◽  
pp. F1405-F1416 ◽  
Author(s):  
Yu Jin Lee ◽  
Han Na Suh ◽  
Ho Jae Han
Keyword(s):  
Protein Expression ◽  
Er Stress ◽  
Proximal Tubule ◽  
Renal Proximal Tubule ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Proximal Tubule Cells ◽  
Eif2α Phosphorylation ◽  
Tubule Cells ◽  
Renal Proximal Tubule Cells

Recent studies demonstrated that endoplasmic reticulum (ER) stress regulates glucose homeostasis and that ER stress preconditioning which induces an adaptive, protective unfolded protein response (UPR) offers cytoprotection against nephrotoxins. Thus the aim of the present study was to use renal proximal tubule cells (PTCs) to further elucidate the link between the BSA-induced ER stress and α-methyl-d-glucopyranoside (α-MG) uptake and to identify related signaling pathways. Among ER stress inducers such as high glucose, BSA, H2O2, or tumicamycin, BSA pretreatment ameliorated the reduction of Na+-glucose cotransporter (SGLT) expression and α-MG uptake by gentamicin or cyclosporine A. Immunofluorescence studies revealed that BSA (10 mg/ml) stimulated the expression of glucose-regulated protein 78 (GRP78), an ER stress biomarker. In addition, BSA increased levels of GRP78 protein expression and eukaryotic initiation factor 2α (eIF2α) phosphorylation in a time-dependent manner. Furthermore, transfection with a GRP78-specific small interfering RNA (siRNA) inhibited BSA-stimulated SGLT expression and α-MG uptake. In experiments designed to unravel the mechanisms underlying BSA-induced ER stress, BSA stimulated the production of cellular reactive oxygen species (ROS), and antioxidants such as ascorbic acid or N-acetylcysteine (NAC) blocked BSA-induced increases in GRP78 activation, eIF2α phosphorylation, SGLT expression, and α-MG uptake. Moreover, the cells upregulated peroxisome proliferator-activated receptor-γ (PPARγ) mRNA levels in response to BSA or troglitazone (a PPARγ agonist), but BSA was ineffective in the presence of GW9662 (a PPARγ antagonist). In addition, both BSA and troglitazone stimulated GRP78 and eIF2α activation, SGLT expression, and α-MG uptake, whereas GW9662 inhibited the effects of BSA. BSA also stimulated phosphorylation of JNK and NF-κB, and GW9662 or GRP78 siRNA attenuated this response. Moreover, SP600125 or SN50 effectively blocked SGLT expression and α-MG uptake in BSA- or PPARγ agonists (troglitazone or PGJ2)-treated PTCs. We conclude that BSA induces ER stress through ROS production and PPARγ activation, which subsequently activates JNK/NF-κB signaling to enhance glucose uptake in renal PTCs.

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