INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, Paris, France; Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, UNAM and Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, Paris, France.
Kidney Int. 2018 Jun;93(6):1344-1355. doi: 10.1016/j.kint.2017.12.016. Epub 2018 Mar 13.
Acute kidney injury induced by ischemia/reperfusion is an independent risk factor for chronic kidney disease. Macrophage recruitment plays an essential role during the injury and repair phases after an ischemic episode in the kidney. Here we show that the novel non-steroidal mineralocorticoid receptor antagonist finerenone or selective myeloid mineralocorticoid receptor ablation protects against subsequent chronic dysfunction and fibrosis induced by an episode of bilateral kidney ischemia/reperfusion in mice. This protection was associated with increased expression of M2-antiinflamatory markers in macrophages from finerenone-treated or myeloid mineralocorticoid receptor-deficient mice. Moreover, the inflammatory population of CD11b, F4/80, Ly6C macrophages was also reduced. Mineralocorticoid receptor inhibition promoted increased IL-4 receptor expression and activation in the whole kidney and in isolated macrophages, thereby facilitating macrophage polarization to an M2 phenotype. The long-term protection conferred by mineralocorticoid receptor antagonism was also translated to the Large White pig pre-clinical model. Thus, our studies support the rationale for using mineralocorticoid receptor antagonists in clinical practice to prevent transition of acute kidney injury to chronic kidney disease.
缺血/再灌注引起的急性肾损伤是慢性肾脏病的一个独立危险因素。在肾缺血后的损伤和修复阶段，巨噬细胞的募集起着至关重要的作用。在这里，我们发现新型非甾体类盐皮质激素受体拮抗剂非奈利酮或选择性髓系盐皮质激素受体缺失可预防小鼠双侧肾脏缺血/再灌注后随后发生的慢性功能障碍和纤维化。这种保护与在非奈利酮治疗或髓系盐皮质激素受体缺失的小鼠的巨噬细胞中表达增加的 M2 抗炎标志物有关。此外，CD11b、F4/80、Ly6C 巨噬细胞的炎症群体也减少了。盐皮质激素受体抑制促进了整个肾脏和分离的巨噬细胞中 IL-4 受体的表达和激活，从而促进了巨噬细胞向 M2 表型的极化。盐皮质激素受体拮抗作用带来的长期保护也转化为大白猪临床前模型。因此，我们的研究支持在临床实践中使用盐皮质激素受体拮抗剂来预防急性肾损伤向慢性肾脏病的转变的原理。
