Al-Mazroua Haneen A, Nadeem Ahmed, Attia Sabry M, Bakheet Saleh A, Ahmad Ajaz, Ansari Mushtaq A, Ibrahim Khalid E, Alomar Hatun A, Almutairi Mohammed M, Algarzae Norah K, Mahmoud Mohamed A, Hussein Marwa H, Ahmed Omer M, Ahmad Sheikh F
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Int Immunopharmacol. 2025 Jan 3;145:113787. doi: 10.1016/j.intimp.2024.113787. Epub 2024 Dec 8.
Systemic lupus erythematosus (SLE) is a classic autoimmune disorder that mostly affects young women and involves various organs, such as the skin, joints, central nervous system, and kidneys. WY14643, a selective agonist of peroxisome proliferator-activated receptor-α, has previously shown anti-inflammatory effects in various disease models. However, its effects on lupus nephritis are yet to be explored. Therefore, the efficacy of WY14643 on renal biomarkers and lupus nephritis was assessed in MRL/lpr mice. Flow cytometry was used to examinethe effects of WY14643 on the expression of IL-17A, STAT3, RORγT, IL-21, IL-21R, IL-22, and TNF-α in splenic CD4 T cells. We further investigated the impact of WY14643 on the mRNA expression of IL-17A, STAT3, RORγT, IL-21, IL-21R, IL-22, and TNF-α in kidney tissue via RT-PCR analysis. The administration of WY14643 effectively improved the symptoms of lupus nephritis in MRL/lpr mice. The administration of WY14643 decreased serum albumin, urine protein, serum creatinine, and blood urea nitrogen levels in MRL/lpr mice. WY14643 reduced the levels of inflammatory markers, including CD4IL-17A, CD4STAT3, CD4RORγT, CD4IL-21, CD4IL-21R, CD4IL-22, and CD4TNF-α, in the spleen cells of MRL/lpr mice. Additionally, we discovered that the administration of WY14643 resulted in the suppression of mRNA levels of IL-17A, STAT3, RORγT, IL-21, IL-22, and TNF-α. The current work shows that the suppression of inflammatory cells by WY14643 may effectively reduce autoimmune characteristics, such as renal inflammation, in lupus-prone MRL/lpr mice. Therefore, WY14643, being a specific PPAR-α agonist, shows significant potential as a novel therapeutic option for treatingnephritis associated with SLE, offering hope for future treatments in this challenging field.
系统性红斑狼疮（SLE）是一种典型的自身免疫性疾病，主要影响年轻女性，累及多个器官，如皮肤、关节、中枢神经系统和肾脏。WY14643是过氧化物酶体增殖物激活受体-α的选择性激动剂，此前已在多种疾病模型中显示出抗炎作用。然而，其对狼疮性肾炎的影响尚待探索。因此，在MRL/lpr小鼠中评估了WY14643对肾脏生物标志物和狼疮性肾炎的疗效。采用流式细胞术检测WY14643对脾脏CD4 T细胞中IL-17A、STAT3、RORγT、IL-21、IL-21R、IL-22和TNF-α表达的影响。我们通过逆转录-聚合酶链反应（RT-PCR）分析进一步研究了WY14643对肾脏组织中IL-17A、STAT3、RORγT、IL-21、IL-21R、IL-22和TNF-α mRNA表达的影响。给予WY14643可有效改善MRL/lpr小鼠的狼疮性肾炎症状。给予WY14643可降低MRL/lpr小鼠的血清白蛋白、尿蛋白、血清肌酐和血尿素氮水平。WY14643降低了MRL/lpr小鼠脾脏细胞中炎症标志物的水平，包括CD4IL-17A、CD4STAT3、CD4RORγT、CD4IL-21、CD4IL-21R、CD4IL-22和CD4TNF-α。此外，我们发现给予WY14643可导致IL-17A、STAT3、RORγT、IL-21、IL-22和TNF-α的mRNA水平受到抑制。目前的研究表明，WY14643对炎症细胞的抑制作用可能有效减轻狼疮易感MRL/lpr小鼠的自身免疫特征，如肾脏炎症。因此，作为一种特异性PPAR-α激动剂，WY14643作为治疗与SLE相关肾炎的新型治疗选择具有显著潜力，为这一具有挑战性领域的未来治疗带来了希望。
