Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Belgium.
Am J Physiol Renal Physiol. 2011 Sep;301(3):F486-93. doi: 10.1152/ajprenal.00116.2011. Epub 2011 Jun 8.
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 (Thébault 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.
肾脏镁（Mg(2+)）和钠（Na(+））的丢失是环孢素（CsA）治疗人类的常见副作用，但潜在机制仍不清楚。最近，表皮生长因子（EGF）通过 TRPM6（Thébault S、Alexander RT、Tiel Groenestege WM、Hoenderop JG、Bindels RJ. J Am Soc Nephrol 20: 78-85, 2009）刺激远端卷曲管（DCT）中的 Mg(2+)重吸收。在 DCT 中，肾脏钠排泄的最终调节受噻嗪类敏感的 Na(+)-Cl(-)共转运体（NCC）调节，该转运体受肾素-血管紧张素-醛固酮系统（RAAS）激活。本研究的目的是更深入地了解 CsA 诱导的低镁血症和低钠血症的分子机制。因此，在 CsA 肾毒性的大鼠模型中，分析了 TRPM6、TRPM7、EGF、EGF 受体、claudin-16、claudin-19 和 NCC 的肾脏表达，以及 RAAS 对 NCC 表达的影响，并研究了 EGF 给药对这些参数的影响。CsA 显著降低了 TRPM6、TRPM7、NCC 和 EGF 的肾脏表达，但 claudin-16 和 claudin-19 的表达不受影响。CsA 治疗大鼠的血清醛固酮明显降低。在接受 EGF 治疗的对照组大鼠中，证明了 TRPM6 肾脏表达增加，同时 Mg(2+)的分数排泄（FE Mg(2+））降低。EGF 对 CsA 治疗大鼠的 TRPM6 和 FE Mg(2+）没有显示出这种有益作用。这些数据表明，CsA 治疗通过下调 DCT 中的 TRPM6 影响 Mg(2+)的稳态。此外，CsA 下调 DCT 中的 NCC，同时 RAAS 失活，导致肾脏钠丢失。
