Siavashpour Asma, Khalvati Bahman, Azarpira Negar, Mohammadi Hamidreza, Niknahad Hossein, Heidari Reza
Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.
Toxicol Lett. 2020 May 16;330:144-158. doi: 10.1016/j.toxlet.2020.05.012.
Cholestatic liver disease is a clinical complication with a wide range of etiologies. The liver is the primary organ influenced by cholestasis. Other organs, rather than the liver (e.g., kidneys), could also be affected by cholestatic liver disease. Cholestasis-induced renal injury is known as cholemic nephropathy (CN). Although the structural and functional alterations of the kidney in cholestasis have been well described, the cellular and molecular mechanisms of CN are not well understood. Some studies mentioned the role of oxidative stress and mitochondrial impairment in CN. Several cellular targets, including proteins, lipids, and DNA, could be affected by oxidative stress. Poly (ADP-Ribose) polymerase-1 (PARP-1) is an enzyme that its physiological activity plays a fundamental role in DNA repair. However, PARP-1 overexpression is associated with enhanced oxidative stress and cell death. The current study was designed to evaluate the role of PARP-1 activity in the pathogenesis of CN. Bile duct ligated (BDL) rats were treated with nicotinamide (NA) as a PARP-1 inhibitor. Kidney, urine, and plasma samples were collected at scheduled time intervals (3, 7, 14, and 28 days after BDL surgery). Serum and urine biomarkers of kidney injury, markers of oxidative stress and DNA damage, PARP-1 expression and activity in the kidney tissue, inflammatory response, renal fibrosis markers, and kidney histopathological alterations were assessed. Significant changes in the serum and urine biomarkers of kidney injury were evident in the BDL rats. Markers of oxidative stress were increased, and tissue ATP levels and antioxidant capacity were decreased in the kidney of cholestatic animals. A significant increase in PARP-1 expression and activity was evident in BDL rats (3, 7, 14, and 28 days after BDL). Moreover, inflammatory response (IL-1β and TNF-α expression; and myeloperoxidase activity), renal tissue histopathological alterations, and kidney fibrosis (α-SMA and TGF-β expression, as well as collagen deposition) were detected in cholestatic animals. It was found that the PARP-1 inhibitor, NA (50 and 100 mg/kg, i.p), significantly mitigated cholestasis-induced renal injury. The positive effects of NA were more significant at a lower dose and the early stage of CN. These data indicate a pathogenic role for PARP-1 overexpression in CN.
胆汁淤积性肝病是一种病因广泛的临床并发症。肝脏是受胆汁淤积影响的主要器官。除肝脏外的其他器官（如肾脏）也可能受到胆汁淤积性肝病的影响。胆汁淤积诱导的肾损伤称为胆血症肾病（CN）。尽管胆汁淤积时肾脏的结构和功能改变已有充分描述，但CN的细胞和分子机制尚不清楚。一些研究提到氧化应激和线粒体损伤在CN中的作用。包括蛋白质、脂质和DNA在内的几个细胞靶点可能受到氧化应激的影响。聚（ADP - 核糖）聚合酶 - 1（PARP - 1）是一种酶，其生理活性在DNA修复中起重要作用。然而，PARP - 1的过表达与氧化应激增强和细胞死亡有关。本研究旨在评估PARP - 1活性在CN发病机制中的作用。胆管结扎（BDL）大鼠用烟酰胺（NA）作为PARP - 1抑制剂进行治疗。在预定时间间隔（BDL手术后3、7、14和28天）收集肾脏、尿液和血浆样本。评估肾脏损伤的血清和尿液生物标志物、氧化应激和DNA损伤标志物、肾脏组织中PARP - 1的表达和活性、炎症反应、肾纤维化标志物以及肾脏组织病理学改变。BDL大鼠肾脏损伤的血清和尿液生物标志物有明显变化。胆汁淤积动物的肾脏中氧化应激标志物增加，组织ATP水平和抗氧化能力降低。BDL大鼠（BDL后3、7、14和28天）PARP - 1的表达和活性明显增加。此外，在胆汁淤积动物中检测到炎症反应（IL - 1β和TNF - α表达；以及髓过氧化物酶活性）、肾脏组织病理学改变和肾纤维化（α - SMA和TGF - β表达以及胶原蛋白沉积）。发现PARP - 1抑制剂NA（50和100mg/kg，腹腔注射）显著减轻胆汁淤积诱导的肾损伤。NA的积极作用在较低剂量和CN早期更显著。这些数据表明PARP - 1过表达在CN中具有致病作用。
