Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown Medical School, Providence, Rhode Island 02903, USA.
Kidney Int. 2013 Apr;83(4):635-46. doi: 10.1038/ki.2012.447. Epub 2013 Jan 16.
Adrenocorticotropic hormone (ACTH) has a renoprotective effect in chronic kidney disease; however, its effect on acute kidney injury (AKI) remains unknown. In a rat model of tumor necrosis factor (TNF)-induced AKI, we found that ACTH gel prevented kidney injury, corrected acute renal dysfunction, and improved survival. Morphologically, ACTH gel ameliorated TNF-induced acute tubular necrosis, associated with a reduction in tubular apoptosis. While the steroidogenic response to ACTH gel plateaued, the kidney-protective effect continued to increase at even higher doses, suggesting steroid-independent mechanisms. Of note, ACTH also acts as a key agonist of the melanocortin system, with its cognate melanocortin 1 receptor (MC1R) abundantly expressed in renal tubules. In TNF-injured tubular epithelial cells in vitro, ACTH reinstated cellular viability and eliminated apoptosis. This beneficial effect was blunted in MC1R-silenced cells, suggesting that this receptor mediates the anti-apoptotic signaling of ACTH. Moreover, ACTH gel protected mice against cecal ligation puncture-induced septic AKI better than α-melanocyte-stimulating hormone: a protein equal in biological activity to ACTH except for steroidogenesis. Thus, ACTH has additive renoprotective actions achieved by both steroid-dependent mechanisms and MC1R-directed anti-apoptosis. ACTH may represent a novel therapeutic strategy to prevent or treat AKI.
促肾上腺皮质激素（ACTH）对慢性肾脏病有肾保护作用；然而，其对急性肾损伤（AKI）的作用尚不清楚。在肿瘤坏死因子（TNF）诱导的 AKI 大鼠模型中，我们发现 ACTH 凝胶可预防肾损伤、纠正急性肾功能障碍和提高存活率。形态上，ACTH 凝胶改善了 TNF 诱导的急性肾小管坏死，与肾小管凋亡减少有关。虽然 ACTH 凝胶对甾体激素的反应达到平台期，但在更高剂量下，其肾保护作用仍继续增加，提示存在非甾体激素依赖的机制。值得注意的是，ACTH 还作为黑素皮质素系统的关键激动剂发挥作用，其同源黑素皮质素 1 受体（MC1R）在肾小管中大量表达。在体外 TNF 损伤的肾小管上皮细胞中，ACTH 恢复了细胞活力并消除了细胞凋亡。在沉默 MC1R 的细胞中，这种有益作用减弱，表明该受体介导了 ACTH 的抗细胞凋亡信号。此外，ACTH 凝胶对盲肠结扎穿刺诱导的脓毒症 AKI 的保护作用优于α-促黑素细胞激素：一种与 ACTH 生物学活性相等的蛋白，除了甾体生成之外。因此，ACTH 具有通过甾体依赖机制和 MC1R 介导的抗细胞凋亡两种作用来实现的附加肾保护作用。ACTH 可能代表预防或治疗 AKI 的一种新的治疗策略。
