Abstract：
The sodium/proton exchanger-3 (NHE3) plays a major role in acid-base and extracellular volume regulation and is also implicated in calcium homeostasis. As calcium and phosphate balances are closely linked, we hypothesized that there was a functional link between kidney NHE3 activity, calcium, and phosphate balance. Therefore, we examined calcium and phosphate homeostasis in kidney tubule-specific NHE3 knockout mice (NHE3loxloxPax8 mice). Compared to controls, these knockout mice were normocalcemic with no significant difference in urinary calcium excretion or parathyroid hormone levels. Thiazide-induced hypocalciuria was less pronounced in the knockout mice, in line with impaired proximal tubule calcium transport. Knockout mice had greater furosemide-induced calciuresis and distal tubule calcium transport pathways were enhanced. Despite lower levels of the sodium/phosphate cotransporters (NaPi)-2a and -2c, knockout mice had normal plasma phosphate, sodium-dependent 32Phosphate uptake in proximal tubule membrane vesicles and urinary phosphate excretion. Intestinal phosphate uptake was unchanged. Low dietary phosphate reduced parathyroid hormone levels and increased NaPi-2a and -2c abundances in both genotypes, but NaPi-2c levels remained lower in the knockout mice. Gene expression profiling suggested proximal tubule remodeling in the knockout mice. Acutely, indirect NHE3 inhibition using the SGLT2 inhibitor empagliflozin did not affect urinary calcium and phosphate excretion. No differences in femoral bone density or architecture were detectable in the knockout mice. Thus, a role for kidney NHE3 in calcium homeostasis can be unraveled by diuretics, but NHE3 deletion in the kidneys has no major effects on overall calcium and phosphate homeostasis due, at least in part, to compensating mechanisms.
摘要：
钠/质子交换剂3（NHE3）在酸碱和细胞外体积调节中起主要作用，并且还涉及钙稳态。由于钙和磷酸盐的平衡密切相关，我们假设肾脏NHE3活性之间存在功能性联系，钙，和磷酸盐平衡。因此,我们检测了肾小管特异性NHE3基因敲除小鼠(NHE3loxloxPax8小鼠)的钙和磷酸盐稳态.与对照组相比，这些基因敲除小鼠血钙正常,尿钙排泄或甲状旁腺激素水平无显著差异.噻嗪类药物诱导的低钙尿在敲除小鼠中不太明显，与近端小管钙转运受损一致。基因敲除小鼠具有更大的呋塞米诱导的钙排泄，并且远端小管钙转运途径增强。尽管钠/磷酸盐共转运蛋白（NaPi）-2a和-2c的含量较低，基因敲除小鼠的血浆磷酸盐正常，近端小管膜囊泡中的钠依赖性32磷酸盐摄取和尿磷酸盐排泄。肠道磷酸盐摄取没有变化。低饮食磷酸盐降低了甲状旁腺激素水平，并增加了两种基因型的NaPi-2a和-2c丰度，但敲除小鼠的NaPi-2c水平仍然较低。基因表达谱提示敲除小鼠的近端小管重塑。绝对,使用SGLT2抑制剂依帕列净的间接NHE3抑制作用不影响尿钙和磷酸盐的排泄.在敲除小鼠中没有检测到股骨骨密度或结构的差异。因此，肾脏NHE3在钙稳态中的作用可以通过利尿剂来解开，但是肾脏中的NHE3缺失对钙和磷酸盐的整体稳态没有重大影响，至少在某种程度上,补偿机制。
