Cardiorenal protective effects of sodium-glucose cotransporter 2 inhibition in combination with angiotensin II type 1 receptor blockade in salt-sensitive Dahl rats.
Cardiorenal protective effects of sodium-glucose cotransporter 2 inhibition in combination with angiotensin II type 1 receptor blockade in salt-sensitive Dahl rats.
复制标题
钠-葡萄糖协同转运蛋白 2 抑制联合血管紧张素 II 1 型受体阻断对盐敏感 Dahl 大鼠的心肾保护作用。
DOI：
10.1097/hjh.0000000000003099
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Dohi K.
中科院分区：
文献类型：
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作者：
Ito H;Okamoto R;Ali Y;Zhe Y;Katayama K;Ito M;Dohi K.
目的：肾脏通过肾钠转运体调节钠排泄和重吸收，在调节血压盐敏感性中起核心作用。我们假设抑制钠-葡萄糖共转运体2(SGLT2)和阻断血管紧张素II 1型受体(AT1R)可以通过有益于这些转运体的作用而协同减少肾脏的钠重吸收，从而降低血压，改善肾脏和心脏的损害。方法和结果：Dahl盐敏感大鼠分别给予正常盐饮食(0.3%氯化钠)、高盐饮食(8%氯化钠)、高盐饮食加伊拉格列齐(0.04%)、高盐饮食加氯沙坦(0.05%)或高盐饮食加依拉格列黄素和氯沙坦治疗8周。与氯沙坦或伊帕格列齐单药治疗相比，联合治疗显著降低血压，增加每日尿钠排泄量，导致BP盐敏感性的改善比伊帕格列津单药治疗更大。联合治疗明显改善肾小球硬化，减少心肌细胞肥大，与氯沙坦或伊帕格列齐单药治疗相比。结论：单用氯沙坦和联合用药后，肾组织Na+/H+交换器异构体3(NHE3)和Na+-K+-CI−共转运体2(NKCC2)的蛋白表达水平显著降低，而单用依普利嗪则无明显变化。结论：联合应用血管紧张素II受体阻滞剂可通过降低钠转运体NHE3和NKCC2的表达水平，有效地改善血压盐敏感性，从而改善血压盐敏感性和心肾保护作用。
Objective:The kidney plays a central role in regulating the salt sensitivity of blood pressure (BP) by governing sodium excretion and reabsorption via renal sodium transporters. We hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibition and angiotensin II type 1 receptor (AT 1 R) blockade can synergistically reduce renal sodium reabsorption by beneficially effects on these transporters, leading to lower BP and ameliorating renal and cardiac damage.Methods and results:Dahl salt-sensitive rats were treated orally for 8weeks with a normal salt diet (0.3% NaCl), a high-salt diet (8% NaCl), high-salt diet with ipragliflozin (0.04%), high-salt diet with losartan (0.05%) or high-salt diet with a combination of ipragliflozin and losartan. The combination treatment significantly reduced BP and increased daily urine sodium excretion compared with losartan or ipragliflozin monotherapy, leading to greater improvement in BP salt sensitivity than ipragliflozin monotherapy. The combination treatment significantly ameliorated glomerulosclerosis and reduced cardiomyocyte hypertrophy compared with losartan or ipragliflozin monotherapy. The protein expression levels of Na+/H+ exchanger isoform 3 (NHE3) and Na+-K+-CI− cotransporter 2 (NKCC2) in the kidney were significantly decreased with losartan monotherapy and combination treatment, but not with ipragliflozin monotherapy.Conclusion:Inhibition of SGLT2 in combination with an angiotensin II receptor blocker effectively improved BP salt sensitivity by reducing renal expression levels of sodium transporters including NHE3 and NKCC2, which eventually led to improvement of BP salt sensitivity and cardiorenal protection.