Ureteral obstruction in neonatal mice elicits segment-specific tubular cell responses leading to nephron loss
Ureteral obstruction in neonatal mice elicits segment-specific tubular cell responses leading to nephron loss
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DOI：
10.1046/j.1523-1755.2003.00775.x
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发表时间：
2003-02-01
影响因子：
19.6
通讯作者：
Chevalier, RL
中科院分区：
文献类型：
--
作者：
Cachat, F;Lange-Sperandio, B;Chevalier, RL
背景为了阐明梗阻性肾病中肾单位丢失的肾反应顺序，我们研究了新生小鼠慢性单侧输尿管梗阻（UUO）后节段性肾单位细胞变化的演变。对新生小鼠进行UUO或假手术，并在手术后5、12或19天收获肾脏。用凝集素鉴定近端小管（PT）、远端小管（DT）和集合管（CD）。对细胞坏死、凋亡、增殖、肾小管扩张、肾小管基底膜（TBM）增厚、间质胶原和肾小球成熟进行组织形态学定量。以哌莫硝唑为标记物测定缺氧组织的分布。通过机械拉伸小鼠近端肾小管和集合管细胞的单层培养物并测量增殖进行了额外的研究。在整个研究期间，新生儿UUO诱导肾小球成熟停滞。慢性UUO诱导PT缺氧、肾小管坏死、增殖和TBM增厚，但刺激DT和CD的凋亡。梗阻性肾脏中的肾小管扩张在CD中最严重，在PT中最不严重。肾小管上皮细胞凋亡与肾小管扩张密切相关（P < 0.05），个别肾小管周围纤维化也与肾小管扩张相关（P < 0.001）。机械拉伸诱导的小鼠肾小管细胞凋亡与轴向应变的大小成正比：CD细胞的凋亡始终大于PT细胞（P < 0.05）。UUO后，缺氧与PT的细胞增殖、坏死和TBM增厚的共定位与血管收缩引起的缺血性损伤一致。相反，肾单位远端部分（DT和CD）的选择性扩张，这是由于那里的小管顺应性更大，导致牵张诱导的上皮细胞凋亡，沿着进行性小管周围纤维化。梗阻性肾发育过程中的肾单位丢失可能是由复杂的节段特异性细胞反应引起的。
Background. To elucidate the sequence of renal responses leading to nephron loss in obstructive nephropathy, we examined the evolution of segmental nephron cellular changes consequent to chronic unilateral ureteral obstruction (UUO) in the neonatal mouse.Methods. Neonatal mice were subjected to UUO or sham-operation, and kidneys were harvested 5, 12 or 19 days after surgery. Proximal tubules (PT), distal tubules (DT) and collecting ducts (CD) were identified with lectins. Histomorphometric quantitation was made for cellular necrosis, apoptosis, proliferation, tubular dilatation, tubular basement membrane (TBM) thickening, interstitial collagen, and glomerular maturation. The distribution of hypoxic tissue was determined using pimonidazole as a marker. Additional studies were performed by mechanically stretching monolayer cultures of mouse proximal tubular and collecting duct cells, and measuring apoptosis.Results. Neonatal UUO induced an arrest of glomerular maturation throughout the period of study. Chronic UUO induced hypoxia, tubular necrosis, proliferation, and TBM thickening in the PT, but stimulated apoptosis in the DT and CD. Tubular dilation in the obstructed kidney was most severe in CD and least severe in PT. Tubular cell apoptosis closely paralleled tubular dilation (P < 0.05), and fibrosis surrounding individual tubules also correlated with tubular dilation (P < 0.001). Mechanical stretching of cultured mouse tubular cells induced apoptosis directly proportional to the magnitude of axial strain: apoptosis was consistently greater in CD than in PT cells (P < 0.05).Conclusions. Following UUO, the co-localization of hypoxia with cellular proliferation, necrosis, and TBM thickening of the PT is consistent with ischemic injury resulting from vasoconstriction. In contrast, a selective dilation of the distal portion of the nephron (DT and CD), which results from the greater tubular compliance there, leads to stretch-induced epithelial cell apoptosis, along with a progressive peritubular fibrosis. Nephron loss in the obstructed developing kidney likely results from complex, segment-specific cellular responses.