Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, U.S.A.
Department of Biomedical Engineering, University of Virginia Health System, Charlottesville, VA, U.S.A.
Clin Sci (Lond). 2018 Dec 5;132(23):2519-2545. doi: 10.1042/CS20180623. Print 2018 Dec 12.
Congenital obstructive nephropathy is a major cause of chronic kidney disease (CKD) in children. The contribution of changes in the identity of renal cells to the pathology of obstructive nephropathy is poorly understood. Using a partial unilateral ureteral obstruction (pUUO) model in genetically modified neonatal mice, we traced the fate of cells derived from the renal stroma, cap mesenchyme, ureteric bud (UB) epithelium, and podocytes using , and mice respectively, crossed with double fluorescent reporter (membrane-targetted tandem dimer Tomato (mT)/membrane-targetted GFP (mG)) mice. Persistent obstruction leads to a significant loss of tubular epithelium, rarefaction of the renal vasculature, and decreased renal blood flow (RBF). In addition, Forkhead Box D1 (Foxd1)-derived pericytes significantly expanded in the interstitial space, acquiring a myofibroblast phenotype. Degeneration of Sine Oculis Homeobox Homolog 2 (Six2) and HoxB7-derived cells resulted in significant loss of glomeruli, nephron tubules, and collecting ducts. Surgical release of obstruction resulted in striking regeneration of tubules, arterioles, interstitium accompanied by an increase in blood flow to the level of sham animals. Contralateral kidneys with remarkable compensatory response to kidney injury showed an increase in density of arteriolar branches. Deciphering the mechanisms involved in kidney repair and regeneration post relief of obstruction has potential therapeutic implications for infants and children and the growing number of adults suffering from CKD.
先天性梗阻性肾病是儿童慢性肾脏病（CKD）的主要原因。肾脏细胞特性改变对梗阻性肾病病理的影响知之甚少。我们使用基因修饰的新生小鼠部分单侧输尿管梗阻（pUUO）模型，分别使用、和 小鼠（与双荧光报告（膜靶向串联二聚体番茄（mT）/膜靶向 GFP（mG））小鼠杂交）追踪来源于肾间质、帽状间充质、输尿管芽（UB）上皮和足细胞的细胞命运。持续的梗阻导致肾小管上皮细胞大量丢失、肾血管稀疏和肾血流量（RBF）减少。此外，Foxd1 衍生的周细胞在间质中显著扩张，获得肌成纤维细胞表型。Sine Oculis Homeobox Homolog 2（Six2）和 HoxB7 衍生细胞的变性导致肾小球、肾小管和收集管显著丢失。梗阻解除后的手术释放导致小管、小动脉和间质的显著再生，并使血流增加到假手术动物的水平。对肾损伤有显著代偿反应的对侧肾脏，其小动脉分支密度增加。阐明梗阻解除后肾脏修复和再生所涉及的机制，对婴儿和儿童以及越来越多的 CKD 成年患者具有潜在的治疗意义。
