Inhibitors of the proximal tubular sodium glucose cotransporter SGLT2 are natriuretic and they lower blood pressure. There are reports that the activities of SGLT2 and the Na⁺-H⁺-exchanger, NHE3, are coordinated. If so, then part of the natriuretic response to an SGLT2 inhibitor is mediated by suppressing NHE3. To examine this further, we compared the effects of the SGLT2 inhibitor, empagliflozin, on urine composition and systolic blood pressure (SBP) in non-diabetic mice with tubule-specific NHE3 knock-down (NHE3-ko) and wild-type littermates (WT). A single dose of empagliflozin, titrated to cause minimal glucosuria, increased urinary excretion of Na⁺ and bicarbonate, and raised urine pH in WT, but not in NHE3-ko. Chronic empagliflozin treatment tended to lower SBP despite higher renal renin mRNA expression, and lowered the ratio of SBP to renin mRNA, indicating volume loss. This effect of empagliflozin depended on tubular NHE3. In diabetic Akita mice, chronic empagliflozin enhanced phosphorylation of NHE3 (S552/S605), changes previously linked to lesser NHE3-mediated reabsorption. Chronic empagliflozin also increased expression of genes involved with renal gluconeogenesis, bicarbonate regeneration, and ammonium formation. While this could reflect compensatory responses to acidification of proximal tubular cells resulting from reduced NHE3 activity, these effects were at least in part independent of tubular NHE3 and potentially indicated metabolic adaptations to urinary glucose loss. Moreover, empagliflozin increased luminal α-ketoglutarate, which may serve to stimulate compensatory distal NaCl reabsorption, while co-generated and excreted ammonium balances urine losses of this "potential bicarbonate". The data implicate NHE3 as a determinant of the natriuretic effect of empagliflozin.

中文翻译：

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管状 Na+-H+-交换剂 NHE3 在 SGLT2 抑制剂恩格列净的利钠作用中的作用。

近端肾小管钠葡萄糖协同转运蛋白 SGLT2 的抑制剂具有利钠作用，可降低血压。有报道称，SGLT2 和 Na ⁺ -H ^{+ -}交换剂 NHE3 的活性是协调的。如果是这样，那么对 SGLT2 抑制剂的部分利钠反应是通过抑制 NHE3 介导的。为了进一步研究这一点，我们比较了 SGLT2 抑制剂恩格列净对肾小管特异性 NHE3 敲低 (NHE3-ko) 和野生型同窝仔鼠的尿液成分和收缩压 (SBP) 的影响。 WT）。恩格列净的单剂量滴定至引起最小糖尿，增加的Na尿排泄⁺和碳酸氢盐，并提高了 WT 中的尿液 pH 值，但在 NHE3-ko 中没有。尽管肾肾素 mRNA 表达较高，但慢性 empagliflozin 治疗倾向于降低 SBP，并降低 SBP 与肾素 mRNA 的比率，表明体积减少。empagliflozin 的这种作用取决于管状 NHE3。在糖尿病 Akita 小鼠中，慢性 empagliflozin 增强了 NHE3 (S552/S605) 的磷酸化，这些变化以前与较少的 NHE3 介导的重吸收有关。慢性恩格列净还增加了与肾糖异生、碳酸氢盐再生和铵形成有关的基因的表达。虽然这可能反映了由于 NHE3 活性降低导致近端肾小管细胞酸化的代偿反应，但这些影响至少部分独立于肾小管 NHE3，并可能表明代谢适应对尿葡萄糖损失。而且，empagliflozin 增加管腔 α-酮戊二酸，这可能有助于刺激代偿性远端 NaCl 重吸收，同时共同生成和排泄的铵平衡这种“潜在碳酸氢盐”的尿液损失。数据表明 NHE3 是恩格列净利钠作用的决定因素。