Maternal High-Fat Diet Programs Renal Peroxisomes and Activates NLRP3 Inflammasome-Mediated Pyroptosis in the Rat Fetus.
Maternal High-Fat Diet Programs Renal Peroxisomes and Activates NLRP3 Inflammasome-Mediated Pyroptosis in the Rat Fetus.
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DOI：
10.2147/jir.s329972
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发表时间：
2021
影响因子：
4.5
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Zhou P;Guan H;Guo Y;Zhu L;Liu X
母亲肥胖会损害后代的肾脏发育和功能，并导致成年后患肾脏疾病的风险增加。本研究旨在探讨母体肥胖大鼠胎肾中过氧化物酶体、氧化应激（OS）和炎性小体之间的联系，并探讨抗氧化剂吡咯喹啉醌（PQQ）的潜在治疗作用。通过给予高脂肪饮食加上补充PQQ（40 mg/kg体重）作为潜在疗法来开发母体肥胖大鼠。高碘酸-希夫染色观察肾组织学变化。分析了近足月胎儿（胚胎第20天）肾脏和肾小管上皮细胞（TEC）中过氧化物酶、脂肪酸β-氧化酶、抗氧化剂以及未折叠蛋白反应（UPR）途径和NLRP 3炎性体的调节剂的表达谱。本研究揭示：1）母体高脂饮食（MHF）导致成年后代血压升高; 2）MHF导致胎肾过氧化物酶体标记物PEX 3和14下调; 3）抗氧化剂SOD 2和过氧化氢酶降低，氧化应激标记物Ephx 2升高; 4）MHF诱导UPR通路激活; 5）KEAP 1-NRF 2通路激活; 6）NLRP 3炎性体的激活导致促炎因子的分泌; 7）在TEC中，PEXs和NLRP 3的变化与组织相似，但UPR和NRF 2途径表现出相反的趋势; 8）抗氧化剂PQQ通过降低ROS水平和抑制胎肾中ER应激和炎性体的激活来减轻母体脂毒性。母体高脂饮食可导致胎肾过氧化物酶体数量减少，随后激活OS和炎性小体，导致胎肾细胞凋亡和焦亡。抗氧化剂PQQ对脂毒性对肾编程的影响具有保护作用，因此是预防母体肥胖诱导的肾编程的潜在候选物。
Maternal obesity impairs kidney development and function of the offspring and leads to a greater risk of kidney disease in adulthood. The present study aimed to investigate the link between peroxisomes, oxidative stress (OS), and inflammasomes in the fetal kidney of maternal obesity rats and to explore the potential therapeutic effects of the antioxidant pyrroloquinoline quinone (PQQ). Maternal obesity rats were developed by administration of a high fat diet plus supplementation with PQQ (40 mg/kg body weight) as a potential therapy. Renal histology was observed by Periodic Acid-Schiff staining. The expression profiles of peroxins, fatty acid β-oxidation enzymes, antioxidants, and the regulators of the unfolded protein response (UPR) pathway and NLRP3 inflammasome were analyzed in the kidneys and tubular epithelial cells (TECs) from near-term fetuses (embryonic day 20). The present work revealed that: 1) a maternal high fat diet (MHF) led to higher blood pressure in adult offspring; 2) MHF led to downregulation of peroxisome markers PEX3 and 14 in fetal kidneys; 3) the antioxidant SOD2 and catalase were decreased, and oxidative stress marker Ephx2 was increased; 4) MHF-induced activation of the UPR pathway; 5) the KEAP1-NRF2 pathway was activated; 6) activation of the NLRP3 inflammasome led to secretion of pro-inflammation factors; 7) in TECs, the changes in PEXs and NLRP3 are similar to tissues, but UPR and NRF2 pathways showed opposite trends; 8) and the antioxidant PQQ alleviated maternal lipotoxicity by decreasing ROS levels and inhibiting activation of ER stress and inflammasome in fetal kidney. A maternal high fat diet decreased the number of peroxisomes, subsequently activated OS and inflammasomes, resulting in pyroptosis and apoptosis in fetal kidney. The antioxidant PQQ served a protective role against the effects of lipotoxicity on kidney programming and, thus, is a potential candidate to prevent maternal obesity-induced renal programming.