Overexpression of Nrf2 in Renal Proximal Tubular Cells Stimulates Sodium-Glucose Co-Transporter 2 Expression and Exacerbates Dysglycemia and Kidney Injury in Diabetic Mice

Diabetes ◽  
2021 ◽  
pp. db201126
Author(s):  
Shuiling Zhao ◽  
Chao-Sheng Lo ◽  
Kana Miyata ◽  
Anindya Ghosh ◽  
Xinping Zhao ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Diabetic Mice ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular

scholarly journals Canagliflozin protects against cisplatin-induced acute kidney injury by AMPK-mediated autophagy in renal proximal tubular cells

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Cheol Ho Park ◽  
Bin Lee ◽  
Myeonggil Han ◽  
Woo Joong Rhee ◽  
Man Sup Kwak ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Protective Effect ◽  
Kidney Injury ◽  
Proximal Tubular Cells ◽  
Cell Viability Assay ◽  
Tubular Cells ◽  
Compound C ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular

AbstractSodium-glucose cotransporter 2 inhibitors, which are recently introduced as glucose-lowering agents, improve cardiovascular and renal outcomes in patients with diabetes mellitus. These drugs also have beneficial effects in various kidney disease models. However, the effect of SGLT2 inhibitors on cisplatin-induced acute kidney injury (AKI) and their mechanism of action need to be elucidated. In this study, we investigated whether canagliflozin protects against cisplatin-induced AKI, depending on adenosine monophosphate-activated protein kinase (AMPK) activation and following induction of autophagy. In the experiments using the HK-2 cell line, cell viability assay and molecular analysis revealed that canagliflozin protected renal proximal tubular cells from cisplatin, whereas addition of chloroquine or compound C abolished the protective effect of canagliflozin. In the mouse model of cisplatin-induced AKI, canagliflozin protected mice from cisplatin-induced AKI. However, treatment with chloroquine or compound C in addition to administration of cisplatin and canagliflozin eliminated the protective effect of canagliflozin. Collectively, these findings indicate that canagliflozin protects against cisplatin-induced AKI by activating AMPK and autophagy in renal proximal tubular cells.

scholarly journals Overexpression of Nrf2 in Renal Proximal Tubular Cells Stimulates Sodium-Glucose Co-Transporter 2 Expression and Exacerbates Dysglycemia and Kidney Injury in Diabetic Mice

2021 ◽  
Author(s):  
Shuiling Zhao ◽  
Chao-Sheng Lo ◽  
Kana N. Miyata ◽  
Anindya Ghosh ◽  
Xinping Zhao ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Promoter Activity ◽  
Kidney Injury ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Patients With Diabetes ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular ◽  
The Impact

We investigated the impact of nuclear factor erythroid 2-related factor 2 (Nrf2) overexpression in renal proximal tubular cells (RPTCs) on blood glucose, kidney injury and sodium-glucose co-transporter 2 (Sglt2) expression in diabetic Akita <i>Nrf2</i><sup>-/-</sup>/<i>Nrf2<sup>RPTC</sup></i> transgenic (Tg) mice. Immortalized human RPTCs (HK2) stably transfected with plasmid containing the <i>SGLT2</i> promoter, human kidneys from patients with diabetes were also studied. Nrf2 overexpression was associated with increased blood glucose, glomerular filtration rate, urinary albumin-creatinine ratio, tubulointerstitial fibrosis and Sglt2 expression in Akita <i>Nrf2</i><sup>-/-</sup>/<i>Nrf2<sup>RPTC</sup></i> Tg mice compared to their Akita <i>Nrf2</i><sup>-/-</sup> littermates. <i>In vitro</i>, oltipraz or transfection of <i>NRF2</i> cDNA stimulated SGLT2 expression and <i>SGLT2</i> promoter activity in HK2, and these effects were inhibited by trigonelline or <i>NRF2 </i>small interfering RNA. The deletion of the <i>NRF2</i>-<i>responsive element (NRF2-RE)</i> in the <i>SGLT2</i> promoter abolished the stimulatory effect of oltipraz on <i>SGLT2 </i>promoter activity. NRF2 binding to the <i>NRF2</i>-<i>RE</i> of the <i>SGLT2</i> promoter was confirmed by gel mobility shift assay and chromatin immunoprecipitation assays. Kidneys from patients with diabetes exhibited higher levels of NRF2 and SGLT2 in the RPTCs than kidneys from patients without diabetes. These results suggest a link by which NRF2 mediates hyperglycemia-stimulation of SGLT2 expression and exacerbates blood glucose and kidney injury in diabetes.

scholarly journals Overexpression of Nrf2 in Renal Proximal Tubular Cells Stimulates Sodium-Glucose Co-Transporter 2 Expression and Exacerbates Dysglycemia and Kidney Injury in Diabetic Mice

2021 ◽  
Author(s):  
Shuiling Zhao ◽  
Chao-Sheng Lo ◽  
Kana N. Miyata ◽  
Anindya Ghosh ◽  
Xinping Zhao ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Promoter Activity ◽  
Kidney Injury ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Patients With Diabetes ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular ◽  
The Impact

We investigated the impact of nuclear factor erythroid 2-related factor 2 (Nrf2) overexpression in renal proximal tubular cells (RPTCs) on blood glucose, kidney injury and sodium-glucose co-transporter 2 (Sglt2) expression in diabetic Akita <i>Nrf2</i><sup>-/-</sup>/<i>Nrf2<sup>RPTC</sup></i> transgenic (Tg) mice. Immortalized human RPTCs (HK2) stably transfected with plasmid containing the <i>SGLT2</i> promoter, human kidneys from patients with diabetes were also studied. Nrf2 overexpression was associated with increased blood glucose, glomerular filtration rate, urinary albumin-creatinine ratio, tubulointerstitial fibrosis and Sglt2 expression in Akita <i>Nrf2</i><sup>-/-</sup>/<i>Nrf2<sup>RPTC</sup></i> Tg mice compared to their Akita <i>Nrf2</i><sup>-/-</sup> littermates. <i>In vitro</i>, oltipraz or transfection of <i>NRF2</i> cDNA stimulated SGLT2 expression and <i>SGLT2</i> promoter activity in HK2, and these effects were inhibited by trigonelline or <i>NRF2 </i>small interfering RNA. The deletion of the <i>NRF2</i>-<i>responsive element (NRF2-RE)</i> in the <i>SGLT2</i> promoter abolished the stimulatory effect of oltipraz on <i>SGLT2 </i>promoter activity. NRF2 binding to the <i>NRF2</i>-<i>RE</i> of the <i>SGLT2</i> promoter was confirmed by gel mobility shift assay and chromatin immunoprecipitation assays. Kidneys from patients with diabetes exhibited higher levels of NRF2 and SGLT2 in the RPTCs than kidneys from patients without diabetes. These results suggest a link by which NRF2 mediates hyperglycemia-stimulation of SGLT2 expression and exacerbates blood glucose and kidney injury in diabetes.

scholarly journals Autophagy Deficiency in Renal Proximal Tubular Cells Leads to an Increase in Cellular Injury and Apoptosis under Normal Fed Conditions

2019 ◽  
Vol 21 (1) ◽  
pp. 155 ◽  
Author(s):  
Chigure Suzuki ◽  
Isei Tanida ◽  
Juan Alejandro Oliva Trejo ◽  
Soichiro Kakuta ◽  
Yasuo Uchiyama
Keyword(s):  
Renal Injury ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular ◽  
Renal Tubular

Renal proximal tubular epithelial cells are significantly damaged during acute kidney injury. Renal proximal tubular cell-specific autophagy-deficient mice show increased sensitivity against renal injury, while showing few pathological defects under normal fed conditions. Considering that autophagy protects the proximal tubular cells from acute renal injury, it is reasonable to assume that autophagy contributes to the maintenance of renal tubular cells under normal fed conditions. To clarify this possibility, we generated a knock out mouse model which lacks Atg7, a key autophagosome forming enzyme, in renal proximal tubular cells (Atg7flox/flox;KAP-Cre+). Analysis of renal tissue from two months old Atg7flox/flox;KAP-Cre+ mouse revealed an accumulation of LC3, binding protein p62/sequestosome 1 (a selective substrate for autophagy), and more interestingly, Kim-1, a biomarker for early kidney injury, in the renal proximal tubular cells under normal fed conditions. TUNEL (TdT-mediated dUTP Nick End Labeling)-positive cells were also detected in the autophagy-deficient renal tubular cells. Analysis of renal tissue from Atg7flox/flox;KAP-Cre+ mice at different age points showed that tubular cells positive for p62 and Kim-1 continually increase in number in an age-dependent manner. Ultrastructural analysis of tubular cells from Atg7flox/flox;KAP-Cre+ revealed the presence of intracellular inclusions and abnormal structures. These results indicated that autophagy-deficiency in the renal proximal epithelial tubular cells leads to an increase in injured cells in the kidney even under normal fed conditions.

scholarly journals Kidney Injury Molecule-1 Enhances Endocytosis of Albumin in Renal Proximal Tubular Cells

2015 ◽  
Vol 231 (4) ◽  
pp. 896-907 ◽  
Author(s):  
Xueying Zhao ◽  
Chen Jiang ◽  
Rebecca Olufade ◽  
Dong Liu ◽  
Nerimiah Emmett
Keyword(s):  
Kidney Injury ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular ◽  
Kidney Injury Molecule 1
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