Research Services, Veterans Administration Medical Center, Cincinnati, OH, USA.
Nephrol Dial Transplant. 2012 Apr;27(4):1368-79. doi: 10.1093/ndt/gfr505. Epub 2011 Aug 26.
The epithelial calcium channel (ECaC) (TRPV5) and the Cl-/HCO3- exchanger pendrin (SLC26A4) are expressed on the apical membrane of tubular cells in the distal nephron and play essential roles in calcium re-absorption and bicarbonate secretion, respectively, in the kidney.
A combination of functional and molecular biology techniques were employed to examine the role of pendrin deletion in calcium excretion.
Here, we demonstrate that deletion of pendrin causes acidic urine [urine pH 4.9 in knockout (KO) versus 5.9 in wild-type (WT) mice, P<0.03)] and downregulates the calcium-absorbing molecules ECaC and Na/Ca exchanger in the kidney, as shown by northern hybridization, immunoblot analysis and/or immunofluorescent labeling. These changes were associated with a ∼100% increase in 24-h urine calcium excretion in pendrin null mice. Subjecting the pendrin WT and KO mice to oral bicarbonate loading for 12 days increased the urine pH to ∼8 in both genotypes, normalized the expression of ECaC and Na/Ca exchanger and reduced the urine calcium excretion in pendrin-null mice to levels comparable to WT mice.
We suggest that pendrin dysfunction should be suspected and investigated in humans with an otherwise unexplained acidic urine and hypercalciuria.
上皮钙通道(ECaC)(TRPV5)和氯离子/碳酸氢根交换体 pendrin(SLC26A4)表达在远端肾单位的管状细胞的顶端膜上,分别在肾脏中对钙重吸收和碳酸氢盐分泌起着重要作用。
采用功能和分子生物学技术相结合的方法研究 pendrin 缺失在钙排泄中的作用。
我们在此证明,pendrin 的缺失导致酸性尿液[敲除(KO)组尿液 pH 值为 4.9,而野生型(WT)组为 5.9,P<0.03],并下调了肾脏中的钙吸收分子 ECaC 和 Na/Ca 交换体,这通过 northern 杂交、免疫印迹分析和/或免疫荧光标记得到证实。这些变化与 pendrin 缺失小鼠 24 小时尿钙排泄增加约 100%有关。对 pendrin WT 和 KO 小鼠进行 12 天的口服碳酸氢盐负荷,使两种基因型的尿液 pH 值均增加到约 8,使 ECaC 和 Na/Ca 交换体的表达正常化,并将 pendrin 缺失小鼠的尿钙排泄减少到与 WT 小鼠相当的水平。
我们建议,对于其他原因不明的酸性尿液和高钙尿症患者,应怀疑并研究 pendrin 功能障碍。