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Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment

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Abstract
Renal magnesium (Mg(2+)) and sodium (Na(+)) loss are well-known side effects of cyclosporine (CsA) treatment in humans, but the underlying mechanisms still remain unclear. Recently, it was shown that epidermal growth factor (EGF) stimulates Mg(2+) reabsorption in the distal convoluted tubule (DCT) via TRPM6 (Thebault S, Alexander RT, Tiel Groenestege WM, Hoenderop JG, Bindels RJ. J Am Soc Nephrol 20: 78-85, 2009). In the DCT, the final adjustment of renal sodium excretion is regulated by the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC), which is activated by the renin-angiotensin-aldosterone system (RAAS). The aim of this study was to gain more insight into the molecular mechanisms of CsA-induced hypomagnesemia and hyponatremia. Therefore, the renal expression of TRPM6, TRPM7, EGF, EGF receptor, claudin-16, claudin-19, and the NCC, and the effect of the RAAS on NCC expression, were analyzed in vivo in a rat model of CsA nephrotoxicity. Also, the effect of EGF administration on these parameters was studied. CsA significantly decreased the renal expression of TRPM6, TRPM7, NCC, and EGF, but not that of claudin-16 and claudin-19. Serum aldosterone was significantly lower in CsA-treated rats. In control rats treated with EGF, an increased renal expression of TRPM6 together with a decreased fractional excretion of Mg(2+) (FE Mg(2+)) was demonstrated. EGF did not show this beneficial effect on TRPM6 and FE Mg(2+) in CsA-treated rats. These data suggest that CsA treatment affects Mg(2+) homeostasis via the downregulation of TRPM6 in the DCT. Furthermore, CsA downregulates the NCC in the DCT, associated with an inactivation of the RAAS, resulting in renal sodium loss.
Keywords
magnesium, sodium, renin-angiotensin-aldosterone system, claudin-16, claudin-19, EPIDERMAL-GROWTH-FACTOR, ANGIOTENSIN-ALDOSTERONE SYSTEM, NA+-CL-COTRANSPORTER, TRANSPLANT RECIPIENTS, SECONDARY HYPOCALCEMIA, MAGNESIUM TRANSPORT, TREATED RATS, HYPOMAGNESEMIA, NEPHROPATHY, INHIBITOR

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MLA
Ledeganck, Kristien J., et al. “Expression of Renal Distal Tubule Transporters TRPM6 and NCC in a Rat Model of Cyclosporine Nephrotoxicity and Effect of EGF Treatment.” AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, vol. 301, no. 3, 2011, pp. F486–93, doi:10.1152/ajprenal.00116.2011.
APA
Ledeganck, K. J., Boulet, G. A., Horvath, C. A., Vinckx, M., Bogers, J., Van den Bossche, R., … De Winter, B. Y. (2011). Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 301(3), F486–F493. https://doi.org/10.1152/ajprenal.00116.2011
Chicago author-date
Ledeganck, Kristien J, Gaëlle A Boulet, Caroline A Horvath, Marleen Vinckx, Johannes Bogers, Rita Van den Bossche, Gert A Verpooten, and Benedicte Y De Winter. 2011. “Expression of Renal Distal Tubule Transporters TRPM6 and NCC in a Rat Model of Cyclosporine Nephrotoxicity and Effect of EGF Treatment.” AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY 301 (3): F486–93. https://doi.org/10.1152/ajprenal.00116.2011.
Chicago author-date (all authors)
Ledeganck, Kristien J, Gaëlle A Boulet, Caroline A Horvath, Marleen Vinckx, Johannes Bogers, Rita Van den Bossche, Gert A Verpooten, and Benedicte Y De Winter. 2011. “Expression of Renal Distal Tubule Transporters TRPM6 and NCC in a Rat Model of Cyclosporine Nephrotoxicity and Effect of EGF Treatment.” AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY 301 (3): F486–F493. doi:10.1152/ajprenal.00116.2011.
Vancouver
1.
Ledeganck KJ, Boulet GA, Horvath CA, Vinckx M, Bogers J, Van den Bossche R, et al. Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY. 2011;301(3):F486–93.
IEEE
[1]
K. J. Ledeganck et al., “Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment,” AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, vol. 301, no. 3, pp. F486–F493, 2011.
@article{3162378,
  abstract     = {{Renal magnesium (Mg(2+)) and sodium (Na(+)) loss are well-known side effects of cyclosporine (CsA) treatment in humans, but the underlying mechanisms still remain unclear. Recently, it was shown that epidermal growth factor (EGF) stimulates Mg(2+) reabsorption in the distal convoluted tubule (DCT) via TRPM6 (Thebault S, Alexander RT, Tiel Groenestege WM, Hoenderop JG, Bindels RJ. J Am Soc Nephrol 20: 78-85, 2009). In the DCT, the final adjustment of renal sodium excretion is regulated by the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC), which is activated by the renin-angiotensin-aldosterone system (RAAS). The aim of this study was to gain more insight into the molecular mechanisms of CsA-induced hypomagnesemia and hyponatremia. Therefore, the renal expression of TRPM6, TRPM7, EGF, EGF receptor, claudin-16, claudin-19, and the NCC, and the effect of the RAAS on NCC expression, were analyzed in vivo in a rat model of CsA nephrotoxicity. Also, the effect of EGF administration on these parameters was studied. CsA significantly decreased the renal expression of TRPM6, TRPM7, NCC, and EGF, but not that of claudin-16 and claudin-19. Serum aldosterone was significantly lower in CsA-treated rats. In control rats treated with EGF, an increased renal expression of TRPM6 together with a decreased fractional excretion of Mg(2+) (FE Mg(2+)) was demonstrated. EGF did not show this beneficial effect on TRPM6 and FE Mg(2+) in CsA-treated rats. These data suggest that CsA treatment affects Mg(2+) homeostasis via the downregulation of TRPM6 in the DCT. Furthermore, CsA downregulates the NCC in the DCT, associated with an inactivation of the RAAS, resulting in renal sodium loss.}},
  author       = {{Ledeganck, Kristien J and Boulet, Gaëlle A and Horvath, Caroline A and Vinckx, Marleen and Bogers, Johannes and Van den Bossche, Rita and Verpooten, Gert A and De Winter, Benedicte Y}},
  issn         = {{1931-857X}},
  journal      = {{AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY}},
  keywords     = {{magnesium,sodium,renin-angiotensin-aldosterone system,claudin-16,claudin-19,EPIDERMAL-GROWTH-FACTOR,ANGIOTENSIN-ALDOSTERONE SYSTEM,NA+-CL-COTRANSPORTER,TRANSPLANT RECIPIENTS,SECONDARY HYPOCALCEMIA,MAGNESIUM TRANSPORT,TREATED RATS,HYPOMAGNESEMIA,NEPHROPATHY,INHIBITOR}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{F486--F493}},
  title        = {{Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment}},
  url          = {{http://doi.org/10.1152/ajprenal.00116.2011}},
  volume       = {{301}},
  year         = {{2011}},
}

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