Barrera-Chimal Jonatan, André-Grégoire Gwennan, Nguyen Dinh Cat Aurelie, Lechner Sebastian M, Cau Jérôme, Prince Sonia, Kolkhof Peter, Loirand Gervaise, Sauzeau Vincent, Hauet Thierry, Jaisser Frédéric
Unité Mixte de Recherche Scientifique 1138, Team 1, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, Paris, France.
Unité U1082 Ischemie Reperfusion en Transplantation d'Organes Mécanismes et Innovations Thérapeutiques, Institut National de la Santé et de la Recherche Médicale, Université de Poitiers, Poitiers, France.
J Am Soc Nephrol. 2017 Apr;28(4):1216-1226. doi: 10.1681/ASN.2016040477. Epub 2017 Jan 13.
AKI is a frequent complication in hospitalized patients. Unfortunately, there is no effective pharmacologic approach for treating or preventing AKI. In rodents, mineralocorticoid receptor (MR) antagonism prevents AKI induced by ischemia-reperfusion (IR). We investigated the specific role of vascular MR in mediating AKI induced by IR. We also assessed the protective effect of MR antagonism in IR-induced AKI in the Large White pig, a model of human AKI. In mice, MR deficiency in smooth muscle cells (SMCs) protected against kidney IR injury. MR blockade by the novel nonsteroidal MR antagonist, finerenone, or genetic deletion of MR in SMCs associated with weaker oxidative stress production. Moreover, ischemic kidneys had higher levels of Rac1-GTP, required for NADPH oxidase activation, than sham control kidneys, and genetic deletion of Rac1 in SMCs protected against AKI. Furthermore, genetic deletion of MR in SMCs blunted the production of Rac1-GTP after IR. Pharmacologic inhibition of MR also prevented AKI induced by IR in the Large White pig. Altogether, we show that MR antagonism, or deletion of the MR gene in SMCs, limited the renal injury induced by IR through effects on Rac1-mediated MR signaling. The benefits of MR antagonism in the pig provide a rational basis for future clinical trials assessing the benefits of this approach in patients with IR-mediated AKI.
急性肾损伤（AKI）是住院患者常见的并发症。遗憾的是，目前尚无有效的药物治疗或预防AKI的方法。在啮齿动物中，盐皮质激素受体（MR）拮抗作用可预防缺血再灌注（IR）诱导的AKI。我们研究了血管MR在介导IR诱导的AKI中的具体作用。我们还评估了MR拮抗作用对大白猪（一种人类AKI模型）IR诱导的AKI的保护作用。在小鼠中，平滑肌细胞（SMC）中的MR缺陷可预防肾脏IR损伤。新型非甾体MR拮抗剂非奈利酮对MR的阻断，或SMC中MR的基因缺失，与较弱的氧化应激产生相关。此外，缺血肾脏中NADPH氧化酶激活所需的Rac1-GTP水平高于假手术对照肾脏，SMC中Rac1的基因缺失可预防AKI。此外，SMC中MR的基因缺失减弱了IR后Rac1-GTP的产生。MR的药理抑制也可预防大白猪IR诱导的AKI。总之，我们表明MR拮抗作用或SMC中MR基因的缺失，通过对Rac1介导的MR信号传导的影响，限制了IR诱导的肾损伤。MR拮抗作用在猪中的益处为未来评估该方法对IR介导的AKI患者益处的临床试验提供了合理依据。
