Downregulation of renal sodium transporters and tonicity-responsive enhancer binding protein by long-term treatment with cyclosporin A
Downregulation of renal sodium transporters and tonicity-responsive enhancer binding protein by long-term treatment with cyclosporin A
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DOI：
10.1681/asn.2006060664
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发表时间：
2007-02-01
影响因子：
13.6
通讯作者：
Kwon, H. Moo
中科院分区：
文献类型：
--
作者：
Lim, Sun Woo;Ahn, Kyung Ohk;Kwon, H. Moo
张力响应性增强子结合蛋白(TONEBP)是一种受环境张力调节的转录激活因子。TONEBP通过刺激水通道蛋白-2和尿素转运蛋白来保护延髓免受高渗透压的有害影响，并调节尿液浓度。环孢菌素A(CsA)的治疗应用受到肾毒性的限制，表现为肾小球滤过率降低、纤维化和肾小管缺陷，包括尿药浓度降低。最近有报道称，长期的CsA治疗与肾脏TONEBP靶基因的表达减少有关，包括水通道蛋白-2、尿素转运体和醛糖还原酶。这项研究验证了一种假设，即长期的CsA治疗降低了肾髓质间质的盐度/紧张度，这是由于抑制了活性的钠转运体，导致TONEBP下调。CsA治疗7d对TONEBP和肾功能无明显影响。虽然钠转运体的表达发生了变化，但髓质的紧张性似乎没有变化。相反，CsA治疗28d导致TONEBP下调和明显的肾毒性。TONEBP基因的下调涉及其靶基因的表达减少、胞浆移位和转录减少。这与活性钠转运体-钠/钾/氯转运体2(NKCC2)、钠/氯转运体和Na+，K+-ATPase-表达减少有关，同时伴随着钠排泄增加和尿液浓度降低。注射加压素可恢复延髓外区NKCC2的表达及TONEBP的表达和活性。结论：在长期服用CsA的情况下，TONEBP的下调是次要的，而肾髓质的紧张性降低。
Tonicity-responsive enhancer binding protein (TonEBP) is a transcriptional activator that is regulated by ambient tonicity. TonEBP protects the-rental medulla from the deleterious effects of hyperosmolality and regulates the urinary concentration by stimulating aquaporin-2 and urea transporters. The therapeutic use of cyclosporin A (CsA) is limited by nephrotoxicity that is manifested by reduced GFR, fibrosis, and tubular defects, including reduced urinary concentration. It was reported recently that long-term CsA treatment was associated with decreased renal expression of TonEBP target genes, including aquaporin-2, urea transporter, and aldose reductase. This study tested the hypothesis that long-term CsA treatment reduces the salinity/tonicity of the renal medullary interstitium as a result of inhibition of active sodium transporters, leading to downregulation of TonEBP. CsA treatment for 7 d did not affect TonEBP or renal function. Whereas expression of sodium transporters was altered, the medullary tonicity seemed unchanged. Conversely, 28 d of CsA treatment led to downregulation of TonEBP and overt nephrotoxicity. The downregulation of TonEBP involved reduced expression, cytoplasmic shift, and reduced transcription of its target genes. This was associated with reduced expression of active sodium transporters-sodium/potassium/chloride transporter type 2 (NKCC2), sodium/chloride transporter, and Na+,K+-ATPase-along with increased sodium excretion and reduced urinary concentration. Infusion of vasopressin restored the expression of NKCC2 in the outer medulla as well as the expression and the activity of TonEBP. It is concluded that the downregulation of TonEBP in the setting of long-term CsA administration is secondary to the reduced tonicity of the renal medullary interstitium.