Abstract
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 Mg2+ re-absorption in the distal convoluted tubule via the Mg2+ channel TRPM6. This study investigates the role of TRPM Mg2+ channels, claudines, and EGF in the Mg2+ 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 Mg2+. 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 Mg2+ 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 Mg2+ loss in medication-induced nephropathy.
Highlights
About 43% of the patients treated with cisplatin develop hypomagnesemia due to renal magnesium (Mg2+) loss [1]
Rac1 protein expression was stable in all groups at 4 weeks and at 9 weeks. This in vivo study shows that cisplatin downregulates the epidermal growth factor (EGF) and TRPM6 mRNA levels while the fractional excretion (FE) Mg2+ increases and suggests that cisplatin treatment results in a diminished renal Mg2+ re-absorption via the downregulation of the Mg2+ channel TRPM6
The rat model showed an increased serum creatinine and an increased FE Mg2+ after 4 weeks of treatment, conform to what has been seen in other studies [2,17]
Summary
About 43% of the patients treated with cisplatin develop hypomagnesemia due to renal magnesium (Mg2+) loss [1]. It was shown that acute MgCl2 infusions lead to a significantly higher urinary Mg2+ excretion in cisplatin treated rats and humans [2,3]. The Mg2+ depletion enhances cisplatininduced nephrotoxicity, significantly increasing plasma creatinine and plasma urea [4]. The mechanisms underlying these observations have not yet been described. The major site of passive Mg2+ re-absorption is the thick ascending limb (TAL) where 70% of the Mg2+ is reabsorbed. The tight junction proteins claudin-16 ( known as paracellin-1) and claudin-19 are the key players in this paracellular transport [5,6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
