The calcineurin inhibitor FK506 (tacrolimus) is associated with transient metabolic acidosis and altered expression of renal acid-base transport proteins
The calcineurin inhibitor FK506 (tacrolimus) is associated with transient metabolic acidosis and altered expression of renal acid-base transport proteins
复制标题
DOI：
10.1152/ajprenal.90489.2008
复制
发表时间：
2009-08-01
影响因子：
4.2
通讯作者：
Wagner, Carsten A.
中科院分区：
文献类型：
--
作者：
Mohebbi, Nilufar;Mihailova, Marija;Wagner, Carsten A.
莫赫比N，米哈伊洛娃M，瓦格纳CA。钙调神经磷酸酶抑制剂FK506（他克莫司）与短暂性代谢性酸中毒以及肾脏酸碱转运蛋白表达改变有关。《美国生理学杂志 - 肾脏生理学》297卷：F499 - F509，2009年。首次发表于2009年5月13日；doi:10.1152/ajprenal.90489.2008。 - 像FK506（他克莫司）这样的钙调神经磷酸酶抑制剂通常用于移植后的免疫抑制。其使用受到许多副作用的限制，包括肾小管酸中毒（RTA），主要是远端型。在这项研究中，大鼠接受FK506治疗，在基线时（9天后）全身酸碱状态与对照动物相似。然而，饮用氯化铵水溶液2天的FK506治疗大鼠比对照动物发生更严重的代谢性酸中毒。尿液pH更偏碱性，但净酸排泄正常。酸负荷7天后，两组与酸碱平衡相关的所有差异均趋于相等。在基线条件下，IIa型钠 - 磷协同转运蛋白、3型钠/氢交换体以及生电型钠 - 碳酸氢盐协同转运蛋白的蛋白丰度，以及液泡型H⁺ - ATP酶的a4和B2亚基均降低，而代谢性酸中毒的诱导使FK506治疗动物中这些转运蛋白的蛋白丰度增加。同时，在基线时AE1的蛋白表达降低，在FK506大鼠氯化铵负荷期间与潘氏蛋白一起增加。在基线条件下，钠 - 碳酸氢盐协同转运蛋白NBCn1的蛋白丰度降低，但在代谢性酸中毒期间仍保持下调。形态学分析显示，连接小管和皮质集合管中非A型闰细胞的相对数量增加，而主细胞数量减少。此外，FK506影响液泡型H⁺ - ATP酶a4亚基的亚细胞分布，在连接小管和外髓质集合管中管腔定位减少。这些数据表明，FK506影响肾脏中几种主要的酸碱转运蛋白，其使用与短暂性代谢性酸中毒以及关键肾脏酸碱转运蛋白表达改变有关。
Mohebbi N, Mihailova M, Wagner CA. The calcineurin inhibitor FK506 (tacrolimus) is associated with transient metabolic acidosis and altered expression of renal acid-base transport proteins. Am J Physiol Renal Physiol 297: F499-F509, 2009. First published May 13, 2009; doi:10.1152/ajprenal.90489.2008.-Calcineurin inhibitors like FK506 (tacrolimus) are routinely used for immunosuppression following transplantation. Its use is limited by many side effects, including renal tubular acidosis (RTA), mainly of the distal type. In this study, rats were treated with FK506 and at baseline (after 9 days) systemic acid-base status was similar to that in control animals. However, FK506-treated rats given NH4Cl in the drinking water for 2 days developed a more severe metabolic acidosis than control animals. Urine pH was more alkaline, but net acid excretion was normal. After 7 days of acid load, all differences related to acid-base homeostasis were equalized in both groups. Protein abundance of type IIa Na-P-i cotransporter, type 3 Na+/H+ exchanger, and electrogenic Na+-bicarbonate cotransporter, and both a4 and B2 subunits of the vacuolar H+-ATPase were reduced under baseline conditions, while induction of metabolic acidosis enhanced protein abundance of these transporters in FK506-treated animals. In parallel, protein expression of AE1 was reduced at baseline and increased together with pendrin during NH4Cl loading in FK506 rats. Protein abundance of the Na+-bicarbonate cotransporter NBCn1 was reduced under baseline conditions but remained downregulated during metabolic acidosis. Morphological analysis revealed an increase in the relative number of non-type A intercalated cells in the connecting tubule and cortical collecting duct at the expense of principal cells. Additionally, subcellular distribution of the a4 subunit of the vacuolar H+-ATPase was affected by FK506 with less luminal localization in the connecting tubule and outer medullary collecting duct. These data suggest that FK506 impacts on several major acid-base transport proteins in the kidney, and its use is associated with transient metabolic acidosis and altered expression of key renal acid-base transport proteins.