Maternal protein deficiency alters primary cilia length in renal tubular and impairs kidney development in fetal rat.
Maternal protein deficiency alters primary cilia length in renal tubular and impairs kidney development in fetal rat.
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DOI：
10.3389/fnut.2023.1156029
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发表时间：
2023
影响因子：
5
通讯作者：
Liu, Xiaomei
中科院分区：
文献类型：
--
作者：
Wang, Jun;Zhou, Pei;Zhu, Liangliang;Guan, Hongbo;Gou, Jian;Liu, Xiaomei
宫内营养不良损害胚胎肾脏发育，并导致成年后肾脏疾病和高血压，但其潜在机制尚不清楚。采用母体蛋白限制大鼠模型，研究胎鼠肾脏纤毛发生的关键因子和β-连环蛋白途径，分析异常初级纤毛对肾小管上皮细胞的影响。数据显示FGR胎儿肾单位数量减少，肾小管发育不良。FGR胎儿纤毛生成因子IFT88表达上调，DYNLT1表达下调，并伴有肾小管上皮细胞纤毛延长。WNT/β-连环蛋白信号转导的关键配体WNT7b表达下调，β-连环蛋白的核转位减少。促凋亡蛋白表达上调。体外对HK-2细胞的研究表明，过表达IFT88可延长纤毛，抑制β-连环蛋白信号转导。此外，IFT88过表达可抑制细胞增殖，激活自噬，诱导细胞凋亡。抑制自噬部分恢复了纤毛长度和细胞活力。同样，DYNLT1基因敲除导致HK-2细胞纤毛伸长，抑制细胞增殖，促进细胞凋亡。然而，DYNLT1基因敲除诱导的纤毛伸长并不依赖于自噬，而是与活性氧(ROS)的积累有关。我们阐明，宫内蛋白营养不良导致肾小管上皮细胞纤毛发生因子表达紊乱，纤毛伸长，抑制β-连环蛋白信号转导，诱导细胞凋亡，最终影响肾脏发育。
Intrauterine malnutrition impairs embryo kidney development and leads to kidney disease and hypertension in adulthood, yet the underlying mechanism remains unclear. With a maternal protein restriction (MPR) rat model, we investigated the critical ciliogenesis factors and β-catenin pathway in FGR fetal kidneys and analyzed the impact of aberrant primary cilia on renal tubular epithelium. The data showed decreased nephron number and renal tubular dysgenesis in FGR fetus. FGR fetus showed deregulated expression of ciliogenesis factors including upregulation of IFT88 and downregulation of DYNLT1, accompanied with cilia elongation in renal tubular epithelial cells. Wnt7b, the key ligand for Wnt/β-catenin signaling, was downregulated and nuclear translocation of β-catenin was decreased. The proapoptotic protein was upregulated. In vitro study with HK-2 cells showed that overexpression of IFT88 lengthened the cilia, inhibited β-catenin signaling. Besides, IFT88 overexpression suppressed cell proliferation, activated autophagy, and induced cell apoptosis. Inhibition of autophagy partly restored the cilia length and cell viability. Likewise, knockdown of DYNLT1 led to cilia elongation, suppressed cell proliferation, and promoted apoptosis in HK-2 cell. However, the cilia elongation induced by DYNLT1 knockdown was not autophagy-dependent, but associated with reactive oxygen species (ROS) accumulation. We elucidated that intrauterine protein malnutrition led to deregulation of ciliogenesis factors and cilia elongation in renal tubular epithelial, inhibited β-catenin signaling, and induced cell apoptosis and ultimately, compromised kidney development.
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影响因子：
3.7
作者：
Boehlke C;Janusch H;Hamann C;Powelske C;Mergen M;Herbst H;Kotsis F;Nitschke R;Kuehn EW
通讯作者：
Kuehn EW
影响因子：
6
作者：
通讯作者：
--
影响因子：
2.9
作者：
Magee, Thomas R.;Tafti, Sanaz A.;Nast, Cynthia C.
通讯作者：
Nast, Cynthia C.
DOI：
10.1186/s40348-018-0082-5
发表时间：
2018-03-20
期刊：
Molecular and cellular pediatrics
影响因子：
--
作者：
Menendez-Castro C;Rascher W;Hartner A
通讯作者：
Hartner A
影响因子：
6.6
作者：
Palmer, Krysten J.;MacCarthy-Morrogh, Lucy;Smyllie, Nicola;Stephens, David J.
通讯作者：
Stephens, David J.