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Genetic deletion of the kidney sodium/proton exchanger-3 (NHE3) does not alter calcium and phosphate balance due to compensatory responses
Kidney International ( IF 14.8 ) Pub Date : 2024-07-30 , DOI: 10.1016/j.kint.2024.07.013
Søren B Poulsen 1 , Sathish K Murali 2 , Linto Thomas 3 , Adrienne Assmus 1 , Lena L Rosenbæk 1 , Rikke Nielsen 1 , Henrik Dimke 4 , Timo Rieg 5 , Robert A Fenton 1
Affiliation  

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.

中文翻译:


由于代偿反应,肾钠/质子交换剂-3 (NHE3) 的基因缺失不会改变钙和磷酸盐的平衡



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,也与钙稳态有关。由于钙和磷酸盐平衡密切相关,我们假设肾脏 NHE3 活性、钙和磷酸盐平衡之间存在功能联系。因此,我们检查了肾小管特异性 NHE3 敲除小鼠 (NHE3loxloxPax8 小鼠) 的钙和磷酸盐稳态。与对照组相比,这些基因敲除小鼠钙正常,尿钙排泄或甲状旁腺激素水平无显著差异。噻嗪类诱导的低钙尿症在敲除小鼠中不太明显,与近端肾小管钙转运受损一致。敲除小鼠具有更大的呋塞米诱导的钙化,远端肾小管钙转运途径增强。尽管钠/磷酸盐协同转运蛋白 (NaPi)-2a 和 -2c 水平较低,但敲除小鼠的血浆磷酸盐正常,近端小管膜囊泡中钠依赖性 32 磷酸盐摄取和尿磷酸盐排泄。肠道磷酸盐摄取没有变化。低膳食磷酸盐降低了两种基因型的甲状旁腺激素水平并增加了 NaPi-2a 和 -2c 的丰度,但敲除小鼠的 NaPi-2c 水平仍然较低。基因表达谱表明敲除小鼠的近端肾小管重塑。急性地,使用 SGLT2 抑制剂 empagliflozin 间接抑制 NHE3 不会影响尿钙和磷酸盐排泄。在敲除小鼠中未检测到股骨密度或结构的差异。 因此,利尿剂可以揭示肾脏 NHE3 在钙稳态中的作用,但肾脏中的 NHE3 缺失对整体钙和磷酸盐稳态没有重大影响,至少部分是由于代偿机制。
更新日期:2024-07-30
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