Reese Shannon, Vidyasagar Aparna, Jacobson Lynn, Acun Zeki, Esnault Stephane, Hullett Debra, Malter James S, Djamali Arjang
Departments of Medicine and Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
Fibrogenesis Tissue Repair. 2010 Jan 4;3:1. doi: 10.1186/1755-1536-3-1.
Pin 1 is a peptidyl-prolyl isomerase inhibitor related to cyclophilin A and FK506 binding protein (FKBP). Juglone (5-hydroxy-1,4-naphthoquinone) is a natural inhibitor of Pin 1 with anti-inflammatory and antifibrotic properties. We evaluated the role of Pin 1 in renal fibrogenesis by evaluating the effects of juglone on epithelial to mesenchymal transition (EMT) and fibrogenesis in the rat unilateral ureteral obstruction (UUO) model and normal rat tubular epithelial cells (NRK52E).
After 2 weeks of UUO, immunoblot analyses demonstrated that juglone (0.25 and 1 mg/kg/24 h) inhibited the deposition of matrix (alpha-smooth muscle actin (SMA), collagen type III and vimentin) and the activation of signaling pathways involved in fibrogenesis (phospho-smad2) and stress response (phospho-heat shock protein (HSP)27). Juglone also reduced EMT (alpha-SMA and E-cadherin dual staining) and oxidative stress (Mn superoxide dismutase (SOD) and NAPDH oxidase 2 (Nox-2) dual staining) in the obstructed kidney. There was no difference in Pin 1 levels between treatment and control groups. Pin 1 activity was significantly decreased in obstructed kidneys regardless of treatment status. In vitro, juglone (1 muM) significantly decreased alpha-SMA and p-smad levels compared to vehicle.
Juglone attenuates fibrogenesis via Pin 1-independent mechanisms in the UUO model. The antifibrotic effects of juglone may result from the inhibition of smad2 and oxidative stress.
Pin 1是一种与亲环蛋白A和FK506结合蛋白（FKBP）相关的肽基脯氨酰异构酶抑制剂。胡桃醌（5-羟基-1,4-萘醌）是Pin 1的天然抑制剂，具有抗炎和抗纤维化特性。我们通过评估胡桃醌对大鼠单侧输尿管梗阻（UUO）模型和正常大鼠肾小管上皮细胞（NRK52E）上皮-间质转化（EMT）和纤维化的影响，来评估Pin 1在肾纤维化发生中的作用。
UUO 2周后，免疫印迹分析表明，胡桃醌（0.25和1 mg/kg/24 h）抑制基质（α-平滑肌肌动蛋白（SMA）、III型胶原和波形蛋白）的沉积以及参与纤维化形成（磷酸化-smad2）和应激反应（磷酸化热休克蛋白（HSP）27）的信号通路的激活。胡桃醌还减少了梗阻肾脏中的EMT（α-SMA和E-钙黏蛋白双重染色）和氧化应激（锰超氧化物歧化酶（SOD）和NAPDH氧化酶2（Nox-2）双重染色）。治疗组和对照组之间Pin 1水平无差异。无论治疗状态如何，梗阻肾脏中的Pin 1活性均显著降低。在体外，与溶剂相比，胡桃醌（1 μM）显著降低了α-SMA和p-smad水平。
在UUO模型中，胡桃醌通过Pin 1非依赖机制减轻纤维化。胡桃醌的抗纤维化作用可能源于对smad2的抑制和氧化应激。
