Hoogenboom Lieke A, Lely A Titia, Kemp Matthew W, Saito Masatoshi, Jobe Alan H, Wolfs Tim G A M, Schreuder Michiel F
Department of Pediatrics, Maastricht University Medical Centre, Maastricht, Netherlands.
Department of Pediatric Nephrology, Radboudumc Amalia Children's Hospital, Nijmegen, Netherlands.
Front Pediatr. 2022 Apr 4;10:796702. doi: 10.3389/fped.2022.796702. eCollection 2022.
Perinatal complications, such as prematurity and intrauterine growth restriction, are associated with increased risk of chronic kidney disease. Although often associated with reduced nephron endowment, there is also evidence of increased susceptibility for sclerotic changes and podocyte alterations. Preterm birth is frequently associated with chorioamnionitis, though studies regarding the effect of chorioamnionitis on the kidney are scarce. In this study, we aim to unravel the consequences of premature birth and/or perinatal inflammation on kidney development using an ovine model.
In a preterm sheep model, chorioamnionitis was induced by intra-amniotic injection of lipopolysaccharide (LPS) at either 2, 8, or 15 days prior to delivery. Control animals received intra-amniotic injections of sterile saline. All lambs were surgically delivered at 125 days' gestation (full term is 150 days) and immediately euthanized for necropsy. Kidneys were harvested and processed for staining with myeloperoxidase (MPO), Wilms tumor-1 (WT1) and alpha-smooth muscle actine (aSMA). mRNA expression of tumor necrosis factor alpha (), Interleukin 10 (), desmin (), Platelet derived growth factor beta (), Platelet derived growth factor receptor beta (PDGFRB), synaptopodin (SYNPO), and transforming growth factor beta () was measured using quantitative PCR.
Animals with extended (but not acute) LPS exposure had an inflammatory response in the kidney. MPO staining was significantly increased after 8 and 15 days ( = 0.003 and = 0.008, respectively). Expression of ( = 0.016) and ( = 0.026) transcripts was increased, peaking on day 8 after LPS exposure. Glomerular aSMA and expression of TGFB was increased on day 8, suggesting pro-fibrotic mesangial activation, however, this was not confirmed with PDFGB or PDGFRB. The number of WT1 positive nuclei in the glomerulus, as well as expression of synaptopodin, decreased, indicating podocyte injury.
We report that, in an ovine model of prematurity, LPS-induced chorioamnionitis leads to inflammation of the immature kidney. In addition, this process was associated with podocyte injury and there are markers to support pro-fibrotic changes to the glomerular mesangium. These data suggest a potential important role for antenatal inflammation in the development of preterm-associated kidney disease, which is frequent.
围产期并发症，如早产和宫内生长受限，与慢性肾脏病风险增加有关。虽然这些并发症常与肾单位数量减少有关，但也有证据表明其发生硬化性改变和足细胞改变的易感性增加。早产常与绒毛膜羊膜炎有关，不过关于绒毛膜羊膜炎对肾脏影响的研究较少。在本研究中，我们旨在使用绵羊模型来揭示早产和/或围产期炎症对肾脏发育的影响。
在早产绵羊模型中，于分娩前2天、8天或15天经羊膜腔内注射脂多糖（LPS）诱导绒毛膜羊膜炎。对照动物经羊膜腔内注射无菌生理盐水。所有羔羊均在妊娠125天（足月为150天）时通过手术分娩，并立即安乐死进行尸检。采集肾脏并进行处理，用于髓过氧化物酶（MPO）、肾母细胞瘤-1（WT1）和α-平滑肌肌动蛋白（aSMA）染色。使用定量PCR检测肿瘤坏死因子α（TNFα）、白细胞介素10（IL-10）、结蛋白（Desmin）、血小板衍生生长因子β（PDGFB）、血小板衍生生长因子受体β（PDGFRB）、突触足蛋白（SYNPO）和转化生长因子β（TGFβ）的mRNA表达。
长期（而非急性）暴露于LPS的动物肾脏出现炎症反应。8天和15天后MPO染色显著增加（分别为P = 0.003和P = 0.008）。TNFα（P = 0.016）和IL-10（P = 0.026）转录本表达增加，在LPS暴露后第8天达到峰值。第8天肾小球aSMA和TGFβ表达增加，提示促纤维化的系膜激活，然而，PDFGB或PDGFRB未证实这一点。肾小球中WT1阳性核的数量以及突触足蛋白的表达减少，表明足细胞损伤。
我们报告，在早产绵羊模型中，LPS诱导的绒毛膜羊膜炎导致未成熟肾脏发生炎症。此外，这一过程与足细胞损伤有关，并且有标志物支持肾小球系膜的促纤维化改变。这些数据表明产前炎症在常见的早产相关肾脏疾病的发生发展中可能起重要作用。
