Marghani Basma H, El-Adl Mohamed, Ateya Ahmed I, Othman Basma H, Ghamry Heba I, Shukry Mustafa, Soliman Mohamed Mohamed, Rizk Mohamed Abdo
Department of Physiology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt.
Department of Biochemistry, Physiology, and Pharmacology, Faculty of Veterinary Medicine, King Salman International University, South of Sinaa 46612, Egypt.
Metabolites. 2022 Oct 20;12(10):999. doi: 10.3390/metabo12100999.
Cyclosporine A (CSA) is an immunosuppressive drug that has improved transplant survival rates. However, its use is often limited because it is thought to be linked to the development of chronic kidney disease after kidney transplants. This study aimed to investigate the protective effects and underlying mechanisms of physiological unconjugated (UC) hyperbilirubinemia mediated by UGT1A1 antisense oligonucleotide in a mouse model of CsA-induced chronic kidney disease, and match these with that of chitosan (CH) as a natural chelator against kidney injury. In the current study, CsA-treated mice were given an intravenous injection of UGT1A1 antisense morpholino oligonucleotide (16 µg/kg) every third day for 14 days. In serum samples, bilirubin, creatinine, and urea were determined. Markers of oxidative stress, antioxidant activities, and mRNA expression of target genes PPAR-α, cFn, eNOS, NF-B, AT1-R, ETA-R, Kim-1, and NGAL were measured in the kidney tissues. Moreover, histopathological examinations were carried out on the kidney tissue. Physiological UC hyperbilirubinemia could be a promising protective strategy against CsA-induced kidney disease in transplant recipients. UGT1A1 antisense oligonucleotide-induced physiological UC hyperbilirubinemia serum significantly protected against CsA-induced kidney dysfunction. UCB acts as a signaling molecule that protects against kidney disease through different mechanisms, including antioxidant, anti-inflammatory, and hormonal action, by activating nuclear hormone receptors (PPAR-α). Moreover, it significantly downregulated mRNA expression of NF-kB, ETA-R, iNOS, AT1-R, cFn, Kim-1, and NGAL in the kidney tissue and alleviated CsA-induced kidney histological changes in CsA-treated mice.
环孢素A（CSA）是一种免疫抑制药物，它提高了移植存活率。然而，其使用常常受到限制，因为人们认为它与肾移植后慢性肾病的发生有关。本研究旨在探讨在环孢素A诱导的慢性肾病小鼠模型中，由UGT1A1反义寡核苷酸介导的生理性非结合（UC）高胆红素血症的保护作用及其潜在机制，并将其与作为天然螯合剂的壳聚糖（CH）对肾损伤的保护作用进行对比。在本研究中，每隔一天给环孢素A处理的小鼠静脉注射一次UGT1A1反义吗啉代寡核苷酸（16μg/kg），共注射14天。测定血清样本中的胆红素、肌酐和尿素。检测肾组织中氧化应激标志物、抗氧化活性以及靶基因PPAR-α、cFn、eNOS、NF-κB、AT1-R、ETA-R、Kim-1和NGAL的mRNA表达。此外，对肾组织进行组织病理学检查。生理性UC高胆红素血症可能是一种针对移植受者中环孢素A诱导的肾病的有前景的保护策略。UGT1A1反义寡核苷酸诱导的生理性UC高胆红素血症血清显著保护小鼠免受环孢素A诱导的肾功能障碍。非结合胆红素作为一种信号分子，通过激活核激素受体（PPAR-α），通过包括抗氧化、抗炎和激素作用等不同机制来保护肾脏免受疾病侵害。此外，它显著下调肾组织中NF-κB、ETA-R、iNOS、AT1-R、cFn、Kim-1和NGAL的mRNA表达，并减轻环孢素A处理小鼠中环孢素A诱导的肾脏组织学变化。
