Knauf Felix, Thomson Robert B, Heneghan John F, Jiang Zhirong, Adebamiro Adedotun, Thomson Claire L, Barone Christina, Asplin John R, Egan Marie E, Alper Seth L, Aronson Peter S
Departments of Internal Medicine,
Department of Nephrology and Hypertension, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
J Am Soc Nephrol. 2017 Jan;28(1):242-249. doi: 10.1681/ASN.2016030279. Epub 2016 Jun 16.
Patients with cystic fibrosis have an increased incidence of hyperoxaluria and calcium oxalate nephrolithiasis. Net intestinal absorption of dietary oxalate results from passive paracellular oxalate absorption as modified by oxalate back secretion mediated by the SLC26A6 oxalate transporter. We used mice deficient in the cystic fibrosis transmembrane conductance regulator gene (Cftr) to test the hypothesis that SLC26A6-mediated oxalate secretion is defective in cystic fibrosis. We mounted isolated intestinal tissue from C57BL/6 (wild-type) and Cftr mice in Ussing chambers and measured transcellular secretion of [C]oxalate. Intestinal tissue isolated from Cftr mice exhibited significantly less transcellular oxalate secretion than intestinal tissue of wild-type mice. However, glucose absorption, another representative intestinal transport process, did not differ in Cftr tissue. Compared with wild-type mice, Cftr mice showed reduced expression of SLC26A6 in duodenum by immunofluorescence and Western blot analysis. Furthermore, coexpression of CFTR stimulated SLC26A6-mediated Cl-oxalate exchange in Xenopus oocytes. In association with the profound defect in intestinal oxalate secretion, Cftr mice had serum and urine oxalate levels 2.5-fold greater than those of wild-type mice. We conclude that defective intestinal oxalate secretion mediated by SLC26A6 may contribute to the hyperoxaluria observed in this mouse model of cystic fibrosis. Future studies are needed to address whether similar mechanisms contribute to the increased risk for calcium oxalate stone formation observed in patients with cystic fibrosis.
囊性纤维化患者高草酸尿症和草酸钙肾结石的发病率增加。膳食草酸盐的肠道净吸收是由SLC26A6草酸盐转运体介导的草酸盐反向分泌所修饰的被动细胞旁草酸盐吸收导致的。我们使用囊性纤维化跨膜传导调节基因（Cftr）缺陷的小鼠来检验以下假设：在囊性纤维化中，SLC26A6介导的草酸盐分泌存在缺陷。我们将来自C57BL/6（野生型）和Cftr小鼠的离体肠道组织安装在Ussing室中，并测量[C]草酸盐的跨细胞分泌。从Cftr小鼠分离的肠道组织显示出的跨细胞草酸盐分泌明显少于野生型小鼠的肠道组织。然而，另一个代表性的肠道转运过程——葡萄糖吸收，在Cftr组织中并无差异。与野生型小鼠相比，通过免疫荧光和蛋白质印迹分析，Cftr小鼠十二指肠中SLC26A6的表达降低。此外，CFTR的共表达刺激了非洲爪蟾卵母细胞中SLC26A6介导的Cl-草酸盐交换。与肠道草酸盐分泌的严重缺陷相关，Cftr小鼠的血清和尿液草酸盐水平比野生型小鼠高2.5倍。我们得出结论，SLC26A6介导的肠道草酸盐分泌缺陷可能导致了在这种囊性纤维化小鼠模型中观察到的高草酸尿症。未来需要进行研究，以确定类似机制是否导致囊性纤维化患者中观察到的草酸钙结石形成风险增加。
