Paricalcitol prevents MAPK pathway activation and inflammation in adriamycin-induced kidney injury in rats.

IF 1.7 Q3 PATHOLOGY Journal of Pathology and Translational Medicine Pub Date : 2024-09-01 Epub Date: 2024-08-27 DOI:10.4132/jptm.2024.07.12
Amanda Lima Deluque, Lucas Ferreira de Almeida, Beatriz Magalhães Oliveira, Cláudia Silva Souza, Ana Lívia Dias Maciel, Heloísa Della Coletta Francescato, Cleonice Giovanini, Roberto Silva Costa, Terezila Machado Coimbra
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Abstract

Background: Activation of the mitogen-activated protein kinase (MAPK) pathway induces uncontrolled cell proliferation in response to inflammatory stimuli. Adriamycin (ADR)-induced nephropathy (ADRN) in rats triggers MAPK activation and pro-inflammatory mechanisms by increasing cytokine secretion, similar to chronic kidney disease (CKD). Activation of the vitamin D receptor (VDR) plays a crucial role in suppressing the expression of inflammatory markers in the kidney and may contribute to reducing cellular proliferation. This study evaluated the effect of pre-treatment with paricalcitol on ADRN in renal inflammation mechanisms.

Methods: Male Sprague-Dawley rats were implanted with an osmotic minipump containing activated vitamin D (paricalcitol, Zemplar, 6 ng/day) or vehicle (NaCl 0.9%). Two days after implantation, ADR (Fauldoxo, 3.5 mg/kg) or vehicle (NaCl 0.9%) was injected. The rats were divided into four experimental groups: control, n = 6; paricalcitol, n = 6; ADR, n = 7 and, ADR + paricalcitol, n = 7.

Results: VDR activation was demonstrated by increased CYP24A1 in renal tissue. Paricalcitol prevented macrophage infiltration in the glomeruli, cortex, and outer medulla, prevented secretion of tumor necrosis factor-α, and interleukin-1β, increased arginase I and decreased arginase II tissue expressions, effects associated with attenuation of MAPK pathways, increased zonula occludens-1, and reduced cell proliferation associated with proliferating cell nuclear antigen expression. Paricalcitol treatment decreased the stromal cell-derived factor 1α/chemokine C-X-C receptor type 4/β-catenin pathway.

Conclusions: Paricalcitol plays a renoprotective role by modulating renal inflammation and cell proliferation. These results highlight potential targets for treating CKD.

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帕立骨化醇能防止阿霉素诱导的大鼠肾损伤中的 MAPK 通路激活和炎症反应。
背景:有丝分裂原活化蛋白激酶(MAPK)通路的激活可诱导细胞在炎症刺激下发生不受控制的增殖。阿霉素(ADR)诱导的大鼠肾病(ADRN)会通过增加细胞因子分泌引发 MAPK 激活和促炎机制,这与慢性肾病(CKD)类似。维生素 D 受体(VDR)的激活在抑制肾脏炎症标志物的表达方面起着至关重要的作用,并可能有助于减少细胞增殖。本研究评估了帕立骨化醇预处理对肾脏炎症机制中 ADRN 的影响:雄性 Sprague-Dawley 大鼠被植入含有活性维生素 D(paricalcitol,Zemplar,6 纳克/天)或载体(NaCl 0.9%)的渗透性微型泵。植入两天后,注射 ADR(Fauldoxo,3.5 毫克/千克)或载体(氯化钠 0.9%)。大鼠被分为四个实验组:对照组,n = 6;旁卡西妥组,n = 6;ADR 组,n = 7;ADR + 旁卡西妥组,n = 7:结果:肾组织中 CYP24A1 的增加证明了 VDR 的激活。帕立骨化醇能防止巨噬细胞在肾小球、皮质和外髓质中浸润,防止肿瘤坏死因子-α和白细胞介素-1β的分泌,增加精氨酸酶Ⅰ的表达,减少精氨酸酶Ⅱ的表达,这些效应与MAPK通路的衰减有关,增加了封闭带-1,减少了细胞增殖,与增殖细胞核抗原的表达有关。帕立骨化醇治疗可减少基质细胞衍生因子1α/C-X-C受体4型/β-catenin通路:结论:帕立骨化醇通过调节肾脏炎症和细胞增殖发挥肾脏保护作用。这些结果突显了治疗慢性肾脏病的潜在靶点。
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来源期刊
CiteScore
5.00
自引率
4.20%
发文量
45
审稿时长
14 weeks
期刊介绍: The Journal of Pathology and Translational Medicine is an open venue for the rapid publication of major achievements in various fields of pathology, cytopathology, and biomedical and translational research. The Journal aims to share new insights into the molecular and cellular mechanisms of human diseases and to report major advances in both experimental and clinical medicine, with a particular emphasis on translational research. The investigations of human cells and tissues using high-dimensional biology techniques such as genomics and proteomics will be given a high priority. Articles on stem cell biology are also welcome. The categories of manuscript include original articles, review and perspective articles, case studies, brief case reports, and letters to the editor.
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