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IF 10.3 1区医学 Q1 UROLOGY & NEPHROLOGY

Journal of The American Society of Nephrology Pub Date : 2025-04-02 DOI:10.1681/ASN.0000000700

Erika F Jesus, Weverton M Luchi, Paulo C Castro, Flavia L Martins, Marcos V Caetano, Vanderlene L Kung, Antonio C Seguro, James A McCormick, Adriana C C Girardi

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引用次数: 0

摘要

背景：顺铂是一种化疗药物，可诱发肾镁消耗和低镁血症。最近的研究表明，SGLT2 抑制剂可提高糖尿病或非糖尿病患者的血清镁浓度。我们假设SGLT2抑制剂empagliflozin通过作用于镁重吸收的关键部位--粗升支（TAL）和远端曲小管（DCT），从而减轻顺铂诱导的急性低镁血症：成年雄性 Wistar 大鼠每周接受顺铂（2.5 毫克/千克）或生理盐水（载体）治疗，为期五周。三周后，大鼠被随机分配到接受empagliflozin（10毫克/千克/天）或水（载体）治疗，持续15天：结果：顺铂治疗的大鼠出现了明显的低镁血症，镁的部分排泄量（FEMg2+）增加。Empagliflozin 治疗可降低 FEMg2+ 并恢复血清镁水平。在TAL中，顺铂治疗大鼠的NKCC2丰度较高，但磷酸化NKCC2和claudin-16水平低于恩格列净治疗的顺铂大鼠，后者的蛋白质水平与对照组相似。相比之下，顺铂治疗大鼠TAL中的claudin-19丰度高于对照组，且不受empagliflozin治疗的影响。在DCT中，顺铂处理的大鼠显示出NaCl共转运体（NCC）、镁通道TRPM6和NCC磷酸化丰度降低，而所有这些都被empagliflozin所挽救。意想不到的是，经顺铂治疗的大鼠表现出较高的TRPM7 mRNA表达和蛋白丰度，而经empagliflozin治疗的顺铂大鼠的mRNA表达和蛋白丰度与对照组相似。呋塞米或氢氯噻嗪利尿剂挑战试验证实，顺铂治疗大鼠的 NKCC2 和 NCC 活性降低。然而，对照组大鼠和经恩格列净治疗的顺铂大鼠对呋塞米或氢氯噻嗪的利尿反应并无差异。免疫组化表明，恩格列净逆转了顺铂诱导的DCT重塑：结论：Empagliflozin能减少顺铂治疗大鼠肾脏的镁消耗并恢复血清镁，这可能是通过逆转TAL中NKCC2的抑制和claudin-16的下调，同时使DCT中的NCC功能正常化并恢复TRPM6的表达。

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SGLT2 Inhibitors Blunt Kidney Magnesium Wasting in Acute Cisplatin-Induced Hypomagnesemia with Effects on the TAL and DCT.

Background: Cisplatin, a chemotherapeutic agent, induces kidney magnesium wasting and hypomagnesemia. Recent studies suggest that SGLT2 inhibitors elevate serum magnesium concentration in patients with or without diabetes. We hypothesized that the SGLT2 inhibitor empagliflozin attenuates acute cisplatin-induced hypomagnesemia by acting on the thick ascending limb (TAL) and distal convoluted tubule (DCT), key sites of magnesium reabsorption.

Methods: Adult male Wistar rats received weekly treatments of cisplatin (2.5 mg/kg) or saline (vehicle) for five weeks. After three weeks, rats were randomized to receive empagliflozin (10 mg/kg/day) or water (vehicle) for the next fifteen days.

Results: Cisplatin-treated rats developed significant hypomagnesemia with increased fractional excretion of magnesium (FEMg2+). Empagliflozin treatment reduced FEMg2+ and restored serum magnesium levels. In the TAL, cisplatin-treated rats had higher NKCC2 abundance but lower phosphorylated NKCC2 and claudin-16 levels than empagliflozin-treated cisplatin rats, whose protein levels were similar to controls. In contrast, claudin-19 abundance in the TAL was higher in cisplatin-treated rats than in controls and unaffected by empagliflozin treatment. In the DCT, cisplatin-treated rats displayed reduced abundance of the NaCl cotransporter (NCC), the magnesium channel TRPM6, and NCC phosphorylation, all of which were rescued by empagliflozin. Unexpectedly, cisplatin-treated rats exhibited higher mRNA expression and protein abundance of TRPM7 compared to empagliflozin-treated cisplatin rats, whose levels were similar to controls. Diuretic challenge tests with furosemide or hydrochlorothiazide confirmed reduced NKCC2 and NCC activity in cisplatin-treated rats. However, the natriuretic response to furosemide or hydrochlorothiazide did not differ between control and empagliflozin-treated cisplatin rats. Immunohistochemistry suggested that empagliflozin reversed cisplatin-induced DCT remodeling.

Conclusions: Empagliflozin reduces kidney magnesium wasting and restores serum magnesium in cisplatin-treated rats, likely through reversing NKCC2 inhibition and claudin-16 downregulation in the TAL while normalizing NCC function and restoring TRPM6 expression in the DCT.

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来源期刊

Journal of The American Society of Nephrology 医学-泌尿学与肾脏学

CiteScore

22.40

自引率

2.90%

发文量

492

审稿时长

3-8 weeks

期刊介绍： The Journal of the American Society of Nephrology (JASN) stands as the preeminent kidney journal globally, offering an exceptional synthesis of cutting-edge basic research, clinical epidemiology, meta-analysis, and relevant editorial content. Representing a comprehensive resource, JASN encompasses clinical research, editorials distilling key findings, perspectives, and timely reviews. Editorials are skillfully crafted to elucidate the essential insights of the parent article, while JASN actively encourages the submission of Letters to the Editor discussing recently published articles. The reviews featured in JASN are consistently erudite and comprehensive, providing thorough coverage of respective fields. Since its inception in July 1990, JASN has been a monthly publication. JASN publishes original research reports and editorial content across a spectrum of basic and clinical science relevant to the broad discipline of nephrology. Topics covered include renal cell biology, developmental biology of the kidney, genetics of kidney disease, cell and transport physiology, hemodynamics and vascular regulation, mechanisms of blood pressure regulation, renal immunology, kidney pathology, pathophysiology of kidney diseases, nephrolithiasis, clinical nephrology (including dialysis and transplantation), and hypertension. Furthermore, articles addressing healthcare policy and care delivery issues relevant to nephrology are warmly welcomed.