Empagliflozin Inhibits Proximal Tubule NHE3 Activity, Preserves GFR, and Restores Euvolemia in Nondiabetic Rats with Induced Heart Failure
Empagliflozin Inhibits Proximal Tubule NHE3 Activity, Preserves GFR, and Restores Euvolemia in Nondiabetic Rats with Induced Heart Failure
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DOI：
10.1681/asn.2020071029
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发表时间：
2021-07-01
影响因子：
13.6
通讯作者：
Girardi, Adriana C. C.
中科院分区：
文献类型：
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作者：
Borges-Junior, Avio A.;dos Santos, Danubia Silva;Girardi, Adriana C. C.
背景SGLT 2抑制剂可降低心力衰竭（HF）死亡率和发病率的风险，无论是否存在糖尿病，但这种获益的机制仍不清楚。非糖尿病HF大鼠实验验证了SGLT 2抑制剂恩格列净（EMPA）抑制近端小管（PT）NHE 3活性并改善肾脏盐和水处理的假设。4周后，用EMPA处理发生HF的大鼠和假手术大鼠，或另外4周不处理。免疫印迹和定量RT-PCR评价SGLT 2和NHE 3表达。结果EMPA治疗组大鼠血清B型利钠肽水平、右心室重量、肺重/胫骨重均低于对照组。在生理盐水刺激下，EMPA治疗组HF大鼠的利尿和利钠反应与假手术组相似，但高于未治疗组。此外，EMPA治疗防止HF大鼠的GFR下降和肾萎缩。PT NHE 3活性在HF大鼠中高于假手术大鼠，而EMPA治疗显著降低NHE 3活性。出乎意料的是，SGLT 2蛋白和mRNA丰度上调PT的HF rats.Conclusions预防HF进展EMPA与PTNHE 3活性降低，恢复正常血容量，并保存肾质量。此外，PT SGLT 2调节异常可能参与非糖尿病HF的病理生理学。
Background SGLT2 inhibitors reduce the risk of heart failure (HF) mortality and morbidity, regardless of the presence or absence of diabetes, but the mechanisms underlying this benefit remain unclear. Experiments with nondiabetic HF rats tested the hypothesis that the SGLT2 inhibitor empagliflozin (EMPA) inhibits proximal tubule (PT) NHE3 activity and improves renal salt and water handling.Methods Male Wistar rats were subjected to myocardial infarction or sham operation. After 4 weeks, rats that developed HF and sham rats were treated with EMPA or untreated for an additional 4 weeks. Immunoblotting and quantitative RT-PCR evaluated SGLT2 and NHE3 expression. Stationary in vivo microperfusion measured PT NHE3 activity.Results EMPA-treated HF rats displayed lower serum B-type natriuretic peptide levels and lower right ventricle and lung weight to tibia length than untreated HF rats. Uponsaline challenge, the diuretic and natriuretic responses of EMPA-treated HF rats were similar to those of sham rats and were higher than those of untreated HF rats. Additionally, EMPA treatment prevented GFR decline and renal atrophy in HF rats. PT NHE3 activity was higher in HF rats than in sham rats, whereas treatment with EMPA markedly reduced NHE3 activity. Unexpectedly, SGLT2 protein and mRNA abundance were upregulated in the PT of HF rats.Conclusions Prevention of HF progression by EMPA is associated with reduced PTNHE3 activity, restoration of euvolemia, and preservation of renal mass. Moreover, dysregulation of PT SGLT2 may be involved in the pathophysiology of nondiabetic HF.