Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Doi Nephrology & Dialysis Clinic, 5-18-6 Midori, Minami-ku, Hiroshima 734-0005, Japan.
Int J Mol Sci. 2022 Jul 15;23(14):7831. doi: 10.3390/ijms23147831.
The ischemia-reperfusion injury (IRI) of rat kidneys is used as a model of acute kidney injury. Salt-sensitive hypertension occurs in rats after IRI, and the distal nephrons play important roles in the development of this condition. We investigated the role of the mineralocorticoid receptor (MR) in the progression of IRI-induced salt-sensitive hypertension in rats. Fourteen days after right-side nephrectomy, IRI was induced by clamping the left renal artery, with sham surgery performed as a control. IRI rats were provided with normal water or water with 1.0% NaCl (IRI/NaCl), or they were implanted with an osmotic mini-pump to infuse vehicle or aldosterone (IRI/Aldo). Esaxerenone, a non-steroidal MR blocker (MRB), was administered to IRI/NaCl and IRI/Aldo rats for 6 weeks. MR expression increased by day 7 post-IRI. Blood pressure and urinary protein excretion increased in IRI/NaCl and IRI/Aldo rats over the 6-week period, but these effects were negated by MRB administration. The MRB attenuated the expression of the gamma-epithelial sodium channel (ENaC) and renal damage. The ENaC inhibitor, amiloride, ameliorated hypertension and renal damage in IRI/NaCl and IRI/Aldo rats. Our findings thus showed that MR upregulation may play a pivotal role in ENaC-mediated sodium uptake in rats after IRI, resulting in the development of salt-sensitive hypertension in response to salt overload or the activation of the renin-angiotensin-aldosterone system.
肾缺血再灌注损伤（IRI）被用作急性肾损伤的模型。肾缺血再灌注损伤后，大鼠会出现盐敏感性高血压，而远曲小管在这种情况下的发展中起着重要作用。我们研究了盐皮质激素受体（MR）在肾缺血再灌注损伤诱导的盐敏感性高血压大鼠进展中的作用。右侧肾切除术后 14 天，通过夹闭左肾动脉诱导左肾 IRI，假手术作为对照。IRI 大鼠给予正常水或 1.0%NaCl 水（IRI/NaCl），或植入渗透微型泵以输注载体或醛固酮（IRI/Aldo）。依普利酮，一种非甾体类 MR 阻滞剂（MRB），用于 IRI/NaCl 和 IRI/Aldo 大鼠 6 周。IRI 后第 7 天，MR 表达增加。IRI/NaCl 和 IRI/Aldo 大鼠在 6 周期间血压和尿蛋白排泄增加，但 MRB 给药可消除这些影响。MRB 减弱了γ上皮钠通道（ENaC）的表达和肾脏损伤。ENaC 抑制剂氨氯地平可改善 IRI/NaCl 和 IRI/Aldo 大鼠的高血压和肾脏损伤。因此，我们的研究结果表明，MR 上调可能在 IRI 后大鼠的 ENaC 介导的钠摄取中起关键作用，导致盐超负荷或肾素-血管紧张素-醛固酮系统激活时发生盐敏感性高血压。
