Neonatal obstructive nephropathy induces necroptosis and necroinflammation
Neonatal obstructive nephropathy induces necroptosis and necroinflammation
复制标题
DOI：
10.1038/s41598-019-55079-w
复制
发表时间：
2019-12-09
影响因子：
4.6
通讯作者：
Lange-Sperandio, Barbel
中科院分区：
文献类型：
--
作者：
Popper, Bastian;Rammer, Marian Theodor;Lange-Sperandio, Barbel
肾脏发育过程中的尿路梗阻导致肾小管凋亡、肾小管坏死和间质炎症。坏死性凋亡是由受体相互作用丝氨酸/苏氨酸蛋白激酶3（RIPK 3）和假激酶混合谱系激酶结构域样（MLKL）介导的程序性坏死的亚型。坏死诱导炎症并刺激称为坏死性炎症的自动放大环中的细胞死亡。在这里，我们研究了新生C57 Bl/6 J小鼠单侧输尿管梗阻（UUO）引起的梗阻性肾病的坏死性凋亡和坏死性炎症。输尿管梗阻引起肾小管扩张、肾小管基底膜增厚、管型形成和肾损伤分子-1（KIM-1）表达增加。形态学研究表明，无论是凋亡或坏死的细胞在肾小管室。生化分析显示，在UUO-肾脏中caspase-8活性增加，RIPK 3和磷酸化MLKL上调。促炎细胞因子（IL-1 α、INF-γ、TNF-α）在UUO后上调。两者合计，我们表明，坏死性凋亡和坏死性炎症是伴随着新生儿肾脏梗阻的现象。这些发现可能有助于开发治疗先天性梗阻性肾病的新策略。
Urinary tract obstruction during kidney development causes tubular apoptosis, tubular necrosis, and interstitial inflammation. Necroptosis is a subtype of programmed necrosis mediated by the receptor-interacting serine/threonine-protein kinase-3 (RIPK3) and the pseudokinase mixed lineage kinase domain-like (MLKL). Necrosis induces inflammation and stimulates cell death in an autoamplification loop named necroinflammation. Here, we studied necroptosis and necroinflammation in obstructive nephropathy induced by unilateral ureteral obstruction (UUO) in neonatal C57Bl/6J mice. Ureteral obstruction induced tubular dilatation, tubular basement membrane thickening, cast formation, and increased expression of kidney injury molecule-1 (KIM-1). Morphological investigations showed either apoptotic or necrotic cells in the tubular compartment. Biochemical analysis revealed increased caspase-8 activity and upregulation of RIPK3 as well as phosphorylated-MLKL in UUO-kidneys. Pro-inflammatory cytokines (IL-1 alpha, INF-gamma, TNF-alpha) were upregulated following UUO. Taken together we show that necroptosis and necroinflammation are accompanied phenomena in neonatal kidneys with obstruction. These findings may help to develop novel strategies to treat congenital obstructive nephropathy.