The TRPM6/EGF pathway is downregulated in a rat model of cisplatin nephrotoxicity.
Cisplatin-induced hypomagnesemia is described in humans and rats, but the underlying mechanisms are still unclear. Recent studies have shown that epidermal growth factor (EGF) stimulates Mg(2+) re-absorption in the distal convoluted tubule via the Mg(2+) channel TRPM6. This study investigates the ro...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3574071?pdf=render |
| _version_ | 1818043072354713600 |
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| author | Kristien J Ledeganck Gaëlle A Boulet Johannes J Bogers Gert A Verpooten Benedicte Y De Winter |
| author_facet | Kristien J Ledeganck Gaëlle A Boulet Johannes J Bogers Gert A Verpooten Benedicte Y De Winter |
| author_sort | Kristien J Ledeganck |
| collection | DOAJ |
| description | Cisplatin-induced hypomagnesemia is described in humans and rats, but the underlying mechanisms are still unclear. Recent studies have shown that epidermal growth factor (EGF) stimulates Mg(2+) re-absorption in the distal convoluted tubule via the Mg(2+) channel TRPM6. This study investigates the role of TRPM Mg(2+) channels, claudines, and EGF in the Mg(2+) homeostasis in a rat model of cisplatin-induced nephrotoxicity. Wistar rats were given 2.5 mg/kg cisplatin per week for 3 weeks and were euthanized 4 or 9 weeks after the first administration. The cisplatin treatment significantly increased the fractional excretion of Mg(2+). Real-time RT-PCR and/or Western blots were performed to assess the renal expression TRPM6, TRPM7, claudin-16, claudin-19, EGF, EGF receptor (EGFR) and EGFR-pathway components. The renal mRNA expression of TRPM6 and EGF showed a significant decrease after cisplatin treatment, while the TRPM7, claudin-16 and EGFR expressions remained stable. The claudin-19 mRNA expression was significantly upregulated after cisplatin treatment. Western blotting confirmed the mRNA expression data for the claudins, but an showed upregulation of EGFR only at week 9. The role of the EGFR pathway, involving Pi3-AKT-Rac1, in cisplatin-induced nephropathy, could not be substantiated in further detail. This study shows that cisplatin treatment results in EGF and TRPM6 downregulation in the rat kidney, causing renal Mg(2+) loss. Our results are in line with the hypothesis that EGF influences the renal expression or activation of TRPM6 and plays a significant role in Mg(2+) loss in medication-induced nephropathy. |
| first_indexed | 2024-12-10T08:56:24Z |
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| id | doaj.art-9140f8268f014af2a57581a5df8cb3f2 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T08:56:24Z |
| publishDate | 2013-01-01 |
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| series | PLoS ONE |
| spelling | doaj.art-9140f8268f014af2a57581a5df8cb3f22022-12-22T01:55:25ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0182e5701610.1371/journal.pone.0057016The TRPM6/EGF pathway is downregulated in a rat model of cisplatin nephrotoxicity.Kristien J LedeganckGaëlle A BouletJohannes J BogersGert A VerpootenBenedicte Y De WinterCisplatin-induced hypomagnesemia is described in humans and rats, but the underlying mechanisms are still unclear. Recent studies have shown that epidermal growth factor (EGF) stimulates Mg(2+) re-absorption in the distal convoluted tubule via the Mg(2+) channel TRPM6. This study investigates the role of TRPM Mg(2+) channels, claudines, and EGF in the Mg(2+) homeostasis in a rat model of cisplatin-induced nephrotoxicity. Wistar rats were given 2.5 mg/kg cisplatin per week for 3 weeks and were euthanized 4 or 9 weeks after the first administration. The cisplatin treatment significantly increased the fractional excretion of Mg(2+). Real-time RT-PCR and/or Western blots were performed to assess the renal expression TRPM6, TRPM7, claudin-16, claudin-19, EGF, EGF receptor (EGFR) and EGFR-pathway components. The renal mRNA expression of TRPM6 and EGF showed a significant decrease after cisplatin treatment, while the TRPM7, claudin-16 and EGFR expressions remained stable. The claudin-19 mRNA expression was significantly upregulated after cisplatin treatment. Western blotting confirmed the mRNA expression data for the claudins, but an showed upregulation of EGFR only at week 9. The role of the EGFR pathway, involving Pi3-AKT-Rac1, in cisplatin-induced nephropathy, could not be substantiated in further detail. This study shows that cisplatin treatment results in EGF and TRPM6 downregulation in the rat kidney, causing renal Mg(2+) loss. Our results are in line with the hypothesis that EGF influences the renal expression or activation of TRPM6 and plays a significant role in Mg(2+) loss in medication-induced nephropathy.http://europepmc.org/articles/PMC3574071?pdf=render |
| spellingShingle | Kristien J Ledeganck Gaëlle A Boulet Johannes J Bogers Gert A Verpooten Benedicte Y De Winter The TRPM6/EGF pathway is downregulated in a rat model of cisplatin nephrotoxicity. PLoS ONE |
| title | The TRPM6/EGF pathway is downregulated in a rat model of cisplatin nephrotoxicity. |
| title_full | The TRPM6/EGF pathway is downregulated in a rat model of cisplatin nephrotoxicity. |
| title_fullStr | The TRPM6/EGF pathway is downregulated in a rat model of cisplatin nephrotoxicity. |
| title_full_unstemmed | The TRPM6/EGF pathway is downregulated in a rat model of cisplatin nephrotoxicity. |
| title_short | The TRPM6/EGF pathway is downregulated in a rat model of cisplatin nephrotoxicity. |
| title_sort | trpm6 egf pathway is downregulated in a rat model of cisplatin nephrotoxicity |
| url | http://europepmc.org/articles/PMC3574071?pdf=render |
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