Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Department of Pathology, Nationwide Children's Hospital, Columbus, Ohio, USA.
Physiol Rep. 2023 Jul;11(13):e15767. doi: 10.14814/phy2.15767.
Chronic kidney disease (CKD) is characterized by increased interstitial fibrosis and tubular atrophy (IFTA) in the kidney. Chronic hematuria is a hallmark of several human kidney diseases and often is seen in patients on anticoagulation therapy. We had previously demonstrated that chronic hematuria associated with warfarin increases IFTA in 5/6 nephrectomy (5/6NE) rats, and such treatment increases reactive oxygen species (ROS) in the kidney. The goal of this study was to evaluate the effects of the antioxidant N-acetylcysteine (NAC) on the progression of IFTA in 5/6NE mice. 5/6NE C57BL/6 and 5/6NE 129S1/SvImJ mice were treated with warfarin alone or with warfarin and NAC for 23 weeks. Serum creatinine (SCr), hematuria, blood pressure (BP), and ROSs in the kidney were measured; kidney morphology was evaluated. Warfarin doses were titrated to achieve prothrombin time (PT) increase to the levels seen with therapeutic human doses. Warfarin treatment resulted in an increased SCr, systolic BP, hematuria, expression of TGF-ß and ROS in the kidney in both mouse strains. Tumor necrosis factor alpha (TNF-ɑ) levels in the serum were increased in 5/6NE mice treated with warfarin. IFTA was increased as compared with control 5/6NE mice, and this increase in IFTA was more prominent in 129S1/SvImJ than in C57BL/6 mice. NAC ameliorated the warfarin-associated increase in SCr and BP but not hematuria. IFTA, TGF-ß, and ROS in the kidney as well as TNF-ɑ levels in the serum were reduced in mice treated with NAC and warfarin as compared to mice treated with warfarin alone. NAC mitigates the increase in SCr and IFTA in mice with chronic hematuria by reducing oxidative stress in the kidney. This data open novel possibilities for treatments in CKD patients.
慢性肾脏病（CKD）的特征是肾脏间质纤维化和肾小管萎缩（IFTA）增加。慢性血尿是几种人类肾脏疾病的标志，经常出现在接受抗凝治疗的患者中。我们之前已经证明，与华法林相关的慢性血尿会增加 5/6 肾切除（5/6NE）大鼠的 IFTA，并且这种治疗会增加肾脏中的活性氧物种（ROS）。本研究的目的是评估抗氧化剂 N-乙酰半胱氨酸（NAC）对 5/6NE 小鼠 IFTA 进展的影响。用华法林单独或华法林和 NAC 治疗 5/6NE C57BL/6 和 5/6NE 129S1/SvImJ 小鼠 23 周。测量血清肌酐（SCr）、血尿、血压（BP）和肾脏中的 ROS；评估肾脏形态。华法林剂量滴定至达到与治疗性人类剂量相当的凝血酶原时间（PT）增加。华法林治疗导致两种小鼠血清 SCr、收缩压、血尿、TGF-β和肾脏中 ROS 的表达增加。用华法林治疗的 5/6NE 小鼠血清肿瘤坏死因子-α（TNF-ɑ）水平升高。与对照 5/6NE 小鼠相比，IFTA 增加，并且这种 IFTA 的增加在 129S1/SvImJ 小鼠中比在 C57BL/6 小鼠中更为明显。NAC 改善了与华法林相关的 SCr 和 BP 增加，但不能改善血尿。与单独用华法林治疗的小鼠相比，用 NAC 和华法林治疗的小鼠的肾脏 IFTA、TGF-β和 ROS 以及血清 TNF-ɑ水平降低。NAC 通过减少肾脏中的氧化应激减轻慢性血尿小鼠的 SCr 和 IFTA 增加。这些数据为 CKD 患者的治疗开辟了新的可能性。
