School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi, 710069, China.
Division of Nephrology and Hypertension, School of Medicine, University of California Irvine, Irvine, CA, 92897, USA.
Free Radic Biol Med. 2019 Apr;134:484-497. doi: 10.1016/j.freeradbiomed.2019.01.046. Epub 2019 Feb 2.
Renal ischemia-reperfusion injury (IRI) is a complex syndrome, which causes chronic kidney disease (CKD) after recovery from IRI-mediated acute kidney injury (AKI). There is no single therapy that could effectively prevent the renal injury after ischemia. In this study, the effects of melatonin or poricoic acid A (PAA) and their combination were investigated in protecting against AKI-to-CKD transition in rats and hypoxia/reoxygenation (H/R)-induced injury in cultured renal NRK-52E cells. Melatonin and PAA significantly reduced the magnitude of rise in serum creatinine and urea levels in IRI rats at days 3 and 14. Our results further showed that treatment with melatonin and PAA ameliorated renal fibrosis and podocyte injury by attenuating oxidative stress and inflammation via regulation of nuclear factor-kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) pathways in IRI rats. Melatonin and PAA protected against AKI-to-CKD transition by regulating growth arrest-specific 6 (Gas6)/AxlNFκB/Nrf2 signaling cascade. Melatonin and PAA initiallyupregulated Gas6/Axl signaling to reduce oxidative stress and inflammation in AKI and subsequently downregulated Gas6/Axl signaling to attenuate renal fibrosis and progression to CKD. Melatonin and PAA inhibited expression of extracellular matrix proteins. Poricoic acid A enhances melatonin-mediated inhibition of AKI-to-CKD transition by the regulating Gas6/AxlNFκB/Nrf2 signaling cascade. Notably, our study first identified Axl as a promising therapeutic target for prevention of AKI-to-CKD transition.
肾缺血再灌注损伤（IRI）是一种复杂的综合征，它会在 IRI 介导的急性肾损伤（AKI）恢复后导致慢性肾脏病（CKD）。目前没有单一的治疗方法可以有效预防缺血后的肾损伤。在这项研究中，研究了褪黑素或多孔菌酸 A（PAA）及其组合在保护大鼠 AKI 向 CKD 转变和缺氧/复氧（H/R）诱导的培养肾 NRK-52E 细胞损伤中的作用。褪黑素和 PAA 显著降低了 IRI 大鼠在第 3 天和第 14 天血清肌酐和尿素水平升高的幅度。我们的研究结果进一步表明，褪黑素和 PAA 通过调节核因子-κB（NF-κB）和核因子-红细胞 2 相关因子 2（Nrf2）途径来减轻氧化应激和炎症，从而改善 IRI 大鼠的肾纤维化和足细胞损伤。褪黑素和 PAA 通过调节生长停滞特异性 6（Gas6）/AxlNFκB/Nrf2 信号级联来保护 AKI 向 CKD 转变。褪黑素和 PAA 最初通过上调 Gas6/Axl 信号来减少 AKI 中的氧化应激和炎症，随后下调 Gas6/Axl 信号来减轻肾纤维化和向 CKD 的进展。褪黑素和 PAA 抑制细胞外基质蛋白的表达。多孔菌酸 A 通过调节 Gas6/AxlNFκB/Nrf2 信号级联增强褪黑素对 AKI 向 CKD 转变的抑制作用。值得注意的是，我们的研究首次确定 Axl 是预防 AKI 向 CKD 转变的有前途的治疗靶点。
