Advanced Glycated End-Products Affect HIF-Transcriptional Activity in Renal Cells

Advanced glycated end-products (AGEs) are ligands of the receptor for AGEs and increase in diabetic disease. MAPK organizer 1 (Morg1) via its binding partner prolyl-hydroxylase domain (PHD)-3 presumably plays a role in the regulation of hypoxia-inducible factor (HIF)-1α and HIF-2α transcriptional activation. The purpose of this study was to analyze the influence of AGEs on Morg1 expression and its correlation to PHD3 activity and HIF-transcriptional activity in various renal cell types. The addition of glycated BSA (AGE-BSA) significantly up-regulated Morg1 mRNA levels in murine mesangial cells and down-regulated it in murine proximal tubular cells and differentiated podocytes. These effects were reversible when the cells were preincubated with a receptor for α-AGE antibody. AGE-BSA treatment induced a relocalization of the Morg1 cellular distribution compared with nonglycated control-BSA. Analysis of PHD3 activity demonstrated an elevated PHD3 enzymatic activity in murine mesangial cells but an inhibition in murine proximal tubular cells and podocytes after the addition of AGE-BSA. HIF-transcriptional activity was also affected by AGE-BSA treatment. Reporter gene assays and EMSAs showed that AGEs regulate HIF- transcriptional activity under nonhypoxic conditions in a cell type-specific manner. In proximal tubular cells, AGE-BSA stimulation elevated mainly HIF-1α transcriptional activity and to a lesser extent HIF-2α. We also detected an increased expression of the HIF-1α and the HIF-2α proteins in kidneys from Morg1 heterozygous (HZ) placebo mice compared with the Morg1 wild-type (WT) placebo-treated mice, and the HIF-1α protein expression in the Morg1 HZ streptozotocin-treated mice was significantly higher than the WT streptozotocin-treated mice. Analysis of isolated mesangial cells from Morg1 HZ (±) and WT mice showed an inhibited PHD3 activity and an increased HIF-transcriptional activity in cells with only one Morg1 allele. These findings are important for a better understanding of the molecular mechanisms of diabetic nephropathy.

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Intracellular prostaglandin E2 contributes to hypoxia-induced proximal tubular cell death

Scientific Reports ◽

10.1038/s41598-021-86219-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Coral García-Pastor ◽

Selma Benito-Martínez ◽

Ricardo J. Bosch ◽

Ana B. Fernández-Martínez ◽

Francisco J. Lucio-Cazaña

Keyword(s):

Hypoxia Inducible Factor ◽

Renal Diseases ◽

Prostaglandin E ◽

Relevant Factor ◽

Tubular Injury ◽

Proximal Tubular Cells ◽

Tubular Cells ◽

Proximal Tubular ◽

Cox 2 ◽

Induced Apoptosis

AbstractProximal tubular cells (PTC) are particularly vulnerable to hypoxia-induced apoptosis, a relevant factor for kidney disease. We hypothesized here that PTC death under hypoxia is mediated by cyclo-oxygenase (COX-2)-dependent production of prostaglandin E2 (PGE2), which was confirmed in human proximal tubular HK-2 cells because hypoxia (1% O2)-induced apoptosis (i) was prevented by a COX-2 inhibitor and by antagonists of prostaglandin (EP) receptors and (ii) was associated to an increase in intracellular PGE2 (iPGE2) due to hypoxia-inducible factor-1α-dependent transcriptional up-regulation of COX-2. Apoptosis was also prevented by inhibitors of the prostaglandin uptake transporter PGT, which indicated that iPGE2 contributes to hypoxia-induced apoptosis (on the contrary, hypoxia/reoxygenation-induced PTC death was exclusively due to extracellular PGE2). Thus, iPGE2 is a new actor in the pathogenesis of hypoxia-induced tubular injury and PGT might be a new therapeutic target for the prevention of hypoxia-dependent lesions in renal diseases.

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Advanced Glycation End Products Stimulate Angiotensinogen Production in Renal Proximal Tubular Cells

The American Journal of the Medical Sciences ◽

10.1016/j.amjms.2018.10.008 ◽

2019 ◽

Vol 357 (1) ◽

pp. 57-66 ◽

Cited By ~ 4

Author(s):

Joseph M. Garagliano ◽

Akemi Katsurada ◽

Kayoko Miyata ◽

Andrei V. Derbenev ◽

Andrea Zsombok ◽

...

Keyword(s):

Advanced Glycation End Products ◽

Advanced Glycation ◽

Proximal Tubular Cells ◽

Tubular Cells ◽

Glycation End Products ◽

End Products ◽

Proximal Tubular ◽

Renal Proximal Tubular Cells ◽

Renal Proximal Tubular

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Hypoxia induces B-type natriuretic peptide release in cell lines derived from human cardiomyocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00250.2009 ◽

2009 ◽

Vol 297 (2) ◽

pp. H550-H555 ◽

Cited By ~ 44

Author(s):

Gregori Casals ◽

Josefa Ros ◽

Alessandro Sionis ◽

Mercy M. Davidson ◽

Manuel Morales-Ruiz ◽

...

Keyword(s):

Natriuretic Peptide ◽

Transcriptional Activity ◽

Molecular Mechanisms ◽

Ventricular Myocytes ◽

Hypoxia Inducible Factor ◽

Peptide Hormone ◽

Mrna Levels ◽

Human Cardiomyocytes ◽

Hypoxic Conditions

B-type natriuretic peptide (BNP) is a peptide hormone of myocardial origin with significant cardioprotective properties. Patients with myocardial ischemia present with high levels of BNP in plasma and elevated expression in the myocardium. However, the molecular mechanisms of BNP induction in the ischemic myocardium are not well understood. The aim of the investigation was to assess whether myocardial hypoxia induces the production of BNP in human ventricular myocytes. To test the hypothesis that reduced oxygen tension can directly stimulate BNP gene expression and release in the absence of hemodynamic or neurohormonal stimuli, we used an in vitro model system of cultured human ventricular myocytes (AC16 cells). Cells were cultured under normoxic (21% O2) or hypoxic (5% O2) conditions for up to 48 h. The accumulation of BNP, atrial natriuretic peptide (ANP), and vascular endothelial growth factor (VEGF) was then measured. Hypoxia stimulated the protein release of BNP and VEGF but not ANP. In concordance, the increased mRNA levels of BNP and VEGF but not ANP were found on culturing AC16 cells under hypoxic conditions. The analysis of the transcriptional activity of the hypoxia-inducible factor 1 (HIF-1) in nuclear extracts showed that HIF-1 activity was induced under hypoxic conditions. Finally, the treatment of AC16 cells with the HIF-1 inhibitor rotenone in hypoxia inhibited BNP and VEGF release. In conclusion, these data indicate that hypoxia induces the synthesis and secretion of BNP in human ventricular myocytes, likely through HIF-1-enhanced transcriptional activity.

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Molecular mechanisms of glucose action on angiotensinogen gene expression in rat proximal tubular cells

Kidney International ◽

10.1046/j.1523-1755.1999.00271.x ◽

1999 ◽

Vol 55 (2) ◽

pp. 454-464 ◽

Cited By ~ 81

Author(s):

Shao-LING Zhang ◽

Janos G. Filep ◽

Thomas C. Hohman ◽

Shiow-SHIH Tang ◽

Julie R. Ingelfinger ◽

...

Keyword(s):

Gene Expression ◽

Molecular Mechanisms ◽

Proximal Tubular Cells ◽

Tubular Cells ◽

Angiotensinogen Gene ◽

Proximal Tubular

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Cyclosporin A stimulates transcription and procollagen secretion in tubulointerstitial fibroblasts and proximal tubular cells.

Journal of the American Society of Nephrology ◽

10.1681/asn.v16918 ◽

1990 ◽

Vol 1 (6) ◽

pp. 918-922

Author(s):

G Wolf ◽

P D Killen ◽

E G Neilson

Keyword(s):

Cyclosporin A ◽

Gene Product ◽

Transcriptional Activity ◽

Type I ◽

Renal Cells ◽

Proximal Tubular Cells ◽

Tubular Cells ◽

Procollagen Type ◽

Procollagen Type I ◽

Proximal Tubular

The brief study described in this report was undertaken to determine whether cyclosporin A had any direct effect on the expression of tubulointerstitial procollagens in cultured renal cells. Our findings indicate that murine tubulointerstitial fibroblasts secreted significantly more procollagen type I after the addition of cyclosporin A, whereas syngeneic proximal tubular cells expressed significantly more types I and IV procollagen after cyclosporin stimulation. These increases in procollagen gene product correlated concordantly with changes in the levels of cytoplasmic mRNA with procollagen-specific cDNA probes. Transfection of these fibroblasts and proximal tubular cells with chimeric gene constructs containing enhancer/promoter elements for alpha2(I) and alpha 1(IV) procollagen linked to a chloramphenicol acetyltransferase reporter gene indicates that the stimulatory effect of cyclosporin on procollagen expression depends, at least to some extent, on an increase in transcriptional activity.

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Involvement of ERK pathway in albumin-induced MCP-1 expression in mouse proximal tubular cells

AJP Renal Physiology ◽

10.1152/ajprenal.00230.2002 ◽

2003 ◽

Vol 284 (5) ◽

pp. F1037-F1045 ◽

Cited By ~ 72

Author(s):

Kiho Takaya ◽

Daisuke Koya ◽

Motohide Isono ◽

Toshiro Sugimoto ◽

Takeshi Sugaya ◽

...

Keyword(s):

Molecular Mechanisms ◽

Nuclear Factor Κb ◽

Luciferase Reporter ◽

Renal Diseases ◽

Dependent Manner ◽

Nuclear Factor ◽

Proximal Tubular Cells ◽

Tubular Cells ◽

Reporter Activity ◽

Proximal Tubular

Persistent proteinuria has been indicated to be a major risk factor for the development of tubulointerstitial damage through a process of proinflammatory molecule expression. Monocyte chemoattractant protein-1 (MCP-1) was shown to contribute to recruitment of immune cells into the renal interstitium in acute and chronic renal diseases. However, the molecular mechanisms by which proteinuria causes MCP-1 expression in proximal tubular cells have not been fully clarified. In this study, we examined whether albumin overload-induced MCP-1 expression was regulated by mitogen-activated protein kinase (MAPK) in mouse proximal tubular (mProx) cells. Exposure of mProx cells to delipidated bovine serum albumin (BSA) induced mRNA and protein expression of MCP-1 in a time- and dose-dependent manner. BSA activated extracellular signal-regulated kinase (ERK1/2) and p38 MAPK. The MEK inhibitor U-0126 partially suppressed BSA-induced MCP-1 expression and MCP-1 promoter/luciferase reporter activity. U-0126 also inhibited an increase in nuclear factor-κB and activator protein-1 DNA-binding activity of MCP-1 promoter by protein overload in mProx cells. In addition, we found that U-0126 inhibited BSA-induced nuclear factor-κB reporter activity and inhibitory protein degradation in mProx cells. In conclusion, these findings indicate that ERK signaling is involved in BSA-induced MCP-1 expression in mProx cells.

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Mechanism and Consequences of The Impaired Hif-1α Response to Hypoxia in Human Proximal Tubular HK-2 Cells Exposed to High Glucose

Scientific Reports ◽

10.1038/s41598-019-52310-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Coral García-Pastor ◽

Selma Benito-Martínez ◽

Victoria Moreno-Manzano ◽

Ana B. Fernández-Martínez ◽

Francisco Javier Lucio-Cazaña

Keyword(s):

Hypoxia Inducible Factor ◽

Vascular Endothelial ◽

Adaptive Responses ◽

Negative Effects ◽

Proximal Tubular Cells ◽

Tubular Cells ◽

Proximal Tubular ◽

Endothelial Growth Factor ◽

Different Levels

Abstract Renal hypoxia and loss of proximal tubular cells (PTC) are relevant in diabetic nephropathy. Hypoxia inhibits hypoxia-inducible factor-1α (HIF-1α) degradation, which leads to cellular adaptive responses through HIF-1-dependent activation of gene hypoxia-responsive elements (HRE). However, the diabetic microenvironment represses the HIF-1/HRE response in PTC. Here we studied the mechanism and consequences of impaired HIF-1α regulation in human proximal tubular HK-2 cells incubated in hyperglycemia. Inhibition at different levels of the canonical pathway of HIF-1α degradation did not activate the HIF-1/HRE response under hyperglycemia, except when proteasome was inhibited. Further studies suggested that hyperglycemia disrupts the interaction of HIF-1α with Hsp90, a known cause of proteasomal degradation of HIF-1α. Impaired HIF-1α regulation in cells exposed to hyperglycemic, hypoxic diabetic-like milieu led to diminished production of vascular endothelial growth factor-A and inhibition of cell migration (responses respectively involved in tubular protection and repair). These effects, as well as impaired HIF-1α regulation, were reproduced in normoglycemia in HK-2 cells incubated with microparticles released by HK-2 cells exposed to diabetic-like milieu. In summary, these results highlight the role of proteasome-dependent mechanisms of HIF-1α degradation on diabetes-induced HK-2 cells dysfunction and suggest that cell-derived microparticles may mediate negative effects of the diabetic milieu on PTC.

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