Renal sodium and magnesium reabsorption are not coupled in a mouse model of Gordon syndrome.
Renal sodium and magnesium reabsorption are not coupled in a mouse model of Gordon syndrome.
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DOI：
10.14814/phy2.13728
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发表时间：
2018-07
影响因子：
2.5
通讯作者：
van der Wijst J
中科院分区：
文献类型：
--
作者：
van Megen WH;Grimm PR;Welling PA;van der Wijst J
肾脏远曲小管（DCT）中镁（Mg 2+）的主动重吸收对于维持Mg 2+稳态至关重要。Na+-Cl−-协同转运蛋白（NCC）活性受损与高镁尿症和低镁血症相关，而在Gordon综合征患者中观察到的NCC活性增加与Mg 2+平衡改变无关。为了进一步阐明NCC活性和肾脏Mg 2+处理之间可能的相互关系，在Gordon综合征小鼠模型中测量了血浆Mg 2+水平和钠（Na+）和Mg 2+的尿排泄。在该模型中，NCC磷酸化激酶SPAK（CA‐SPAK）组成型活性突变体的DCT 1特异性表达增加了NCC活性和氢氯噻嗪（HCTZ）敏感性Na+重吸收。这些小鼠为正常镁血症，HCTZ给药可显著降低CA‐SPAK小鼠和对照同窝小鼠的血浆Mg 2+水平。根据对HCTZ的初始反应推断，与对照组相比，CA‐SPAK小鼠表现出NCC依赖性Na+重吸收增加以及Mg 2+重吸收减少。在长期HCTZ给药（4天）后，CA‐SPAK小鼠显示尿Mg 2+排泄量较高，而尿Na+排泄量降低至对照动物中观察到的水平。令人惊讶的是，CA-SPAK小鼠的Trpm 6（编码Mg 2+渗透通道TRPM 6）或其他亲镁基因的肾脏表达没有改变。总之，尽管NCC活性和Na+重吸收增加，但CA-SPAK小鼠表现出正常镁血症。因此，Mg 2+重吸收与噻嗪敏感性Na+重吸收增加无关，表明类似的过程解释了Gordon综合征中的正常镁血症。需要进一步的研究来阐明这种现象的分子基础，以及延长HCTZ给药后更明显的Mg 2+排泄。
Active reabsorption of magnesium (Mg2+) in the distal convoluted tubule (DCT) of the kidney is crucial for maintaining Mg2+ homeostasis. Impaired activity of the Na+‐Cl−‐cotransporter (NCC) has been associated with hypermagnesiuria and hypomagnesemia, while increased activity of NCC, as observed in patients with Gordon syndrome, is not associated with alterations in Mg2+ balance. To further elucidate the possible interrelationship between NCC activity and renal Mg2+ handling, plasma Mg2+ levels and urinary excretion of sodium (Na+) and Mg2+ were measured in a mouse model of Gordon syndrome. In this model, DCT1‐specific expression of a constitutively active mutant form of the NCC‐phosphorylating kinase, SPAK (CA‐SPAK), increases NCC activity and hydrochlorothiazide (HCTZ)‐sensitive Na+ reabsorption. These mice were normomagnesemic and HCTZ administration comparably reduced plasma Mg2+ levels in CA‐SPAK mice and control littermates. As inferred by the initial response to HCTZ, CA‐SPAK mice exhibited greater NCC‐dependent Na+ reabsorption together with decreased Mg2+ reabsorption, compared to controls. Following prolonged HCTZ administration (4 days), CA‐SPAK mice exhibited higher urinary Mg2+ excretion, while urinary Na+ excretion decreased to levels observed in control animals. Surprisingly, CA‐SPAK mice had unaltered renal expression of Trpm6, encoding the Mg2+‐permeable channel TRPM6, or other magnesiotropic genes. In conclusion, CA‐SPAK mice exhibit normomagnesemia, despite increased NCC activity and Na+ reabsorption. Thus, Mg2+ reabsorption is not coupled to increased thiazide‐sensitive Na+ reabsorption, suggesting a similar process explains normomagnesemia in Gordon syndrome. Further research is required to unravel the molecular underpinnings of this phenomenon and the more pronounced Mg2+ excretion after prolonged HCTZ administration.