Hypomagnesaemia is a common feature of renal Na⁺ wasting disorders such as Gitelman and EAST/SeSAME syndrome. These genetic defects specifically affect Na⁺ reabsorption in the distal convoluted tubule, where Mg²⁺ reabsorption is tightly regulated. Apical uptake via TRPM6 Mg²⁺ channels and basolateral Mg²⁺ extrusion via a putative Na⁺‐Mg²⁺ exchanger determines Mg²⁺ reabsorption in the distal convoluted tubule. However, the mechanisms that explain the high incidence of hypomagnesaemia in patients with Na⁺ wasting disorders of the distal convoluted tubule are largely unknown. In this review, we describe three potential mechanisms by which Mg²⁺ reabsorption in the distal convoluted tubule is linked to Na⁺ reabsorption. First, decreased activity of the thiazide‐sensitive Na⁺/Cl⁻ cotransporter (NCC) results in shortening of the segment, reducing the Mg²⁺ reabsorption capacity. Second, the activity of TRPM6 and NCC are determined by common regulatory pathways. Secondary effects of NCC dysregulation such as hormonal imbalance, therefore, might disturb TRPM6 expression. Third, the basolateral membrane potential, maintained by the K⁺ permeability and Na⁺‐K⁺‐ATPase activity, provides the driving force for Na⁺ and Mg²⁺ extrusion. Depolarisation of the basolateral membrane potential in Na⁺ wasting disorders of the distal convoluted tubule may therefore lead to reduced activity of the putative Na⁺‐Mg²⁺ exchanger SLC41A1. Elucidating the interconnections between Mg²⁺ and Na⁺ transport in the distal convoluted tubule is hampered by the currently available models. Our analysis indicates that the coupling of Na⁺ and Mg²⁺ reabsorption may be multifactorial and that advanced experimental models are required to study the molecular mechanisms.

中文翻译：

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肾脏远曲小管中钠和镁重吸收的耦合机制。


低镁血症是肾脏 Na ⁺消耗性疾病的常见特征，例如 Gitelman 和 EAST/SeSAME 综合征。这些遗传缺陷特别影响远曲小管中的 Na ⁺重吸收，其中 Mg ²⁺重吸收受到严格调节。通过 TRPM6 Mg ²⁺通道的顶端吸收和通过推定的 Na ⁺ -Mg ²⁺交换器的基底外侧 Mg ²⁺挤出决定了远曲小管中 Mg ^{2+ 的}重吸收。然而，远曲小管Na ⁺消耗性疾病患者低镁血症高发生率的机制尚不清楚。在这篇综述中，我们描述了远曲小管中 Mg ²⁺重吸收与 Na ⁺重吸收相关的三种潜在机制。首先，噻嗪类敏感的 Na ⁺ /Cl ^-协同转运蛋白 (NCC) 活性降低导致片段缩短，从而降低 Mg ²⁺重吸收能力。其次，TRPM6 和 NCC 的活性由共同的调控途径决定。因此，NCC 失调的次要影响（例如激素失衡）可能会干扰 TRPM6 的表达。第三，由K ⁺渗透性和Na ⁺ ‐K ⁺ ‐ATPase 活性维持的基底外侧膜电位，为Na ⁺和Mg ²⁺挤出提供驱动力。 因此，远曲小管 Na ⁺消耗性疾病中基底外侧膜电位的去极化可能导致假定的 Na ⁺ ‐Mg ²⁺交换器 SLC41A1 的活性降低。目前可用的模型阻碍了阐明远曲小管中 Mg ²⁺和 Na ⁺转运之间的相互关系。我们的分析表明Na ⁺和Mg ²⁺重吸收的耦合可能是多因素的，需要先进的实验模型来研究分子机制。