Development of renal failure in PargParp-1 null and Timm23 hypomorphic mice
Development of renal failure in PargParp-1 null and Timm23 hypomorphic mice
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DOI：
10.1016/j.bcp.2019.07.003
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发表时间：
2019-09-01
影响因子：
5.8
通讯作者：
Masutani，Mitsuko
中科院分区：
文献类型：
--
作者：
Chen，Lichao;Gunji，Akemi;Masutani，Mitsuko
聚ADP-核糖糖水解酶（Poly（ADP-ribose）glycohydrolase，Parg）是聚ADP-核糖降解的中心酶。我们通过缺失Parg基因第1外显子的一部分和上游约0.4kb的序列建立了Parg +/−小鼠品系，通过Parg +/−小鼠杂交获得的Parg−/−胚胎在交配后4.5至9.5天死于子宫内。我们研究了聚ADP核糖聚合酶-1（Parp-1）缺陷是否可以挽救Parg −/−小鼠的胚胎致死率。Parg−/−Parp-1−/−小鼠出生存活率低于Parg +/−Parp-1−/−小鼠杂交后代中预期的孟德尔比率。结果表明，Parp-1的存在可能是导致Parg −/−胚胎死亡的原因，而Parg分子或Parg活性降解聚（ADP-核糖）可能对胚胎发生很重要。在Parg −/−Parp-1−/−小鼠中，在各种组织中均未检测到Parg蛋白，并且Parg的5 '上游基因Timm 23的蛋白水平与Parg +/+Parp-1−/−小鼠相比降低。Parg−/−Parp-1−/−小鼠与Parg +/+Parp-1 −/−小鼠相比表现出生长迟缓，并且在3月龄内死亡，伴有严重的肾衰竭。在Parg −/−Parp-1−/−小鼠中观察到肾小球硬化、肾小管扩张和肾透明管型。与Parg +/+Parp-1 −/−小鼠相比，在Parg −/− Parp-1 −/−小鼠中还检测到血尿素氮增加（p <0.05）、尿白蛋白水平显著增加（p< 0.01）及其伴随的血清白蛋白水平降低（p< 0.05）。结果表明，Parg和Parp-1缺失与Timm 23的亚形态状态的结合导致严重肾衰竭的发展。
Poly(ADP-ribose) glycohydrolase (Parg) is a central enzyme for poly(ADP-ribose) degradation. We established aParg+/−mice strain by deletion of a part of exon 1 and around 0.4-kb upstream of sequences of theParggene.Parg−/−embryos obtained by intercrossing theParg+/−mice died in utero between 4.5 and 9.5 days postcoitum. We examined whether poly(ADP-ribose) polymerase-1 (Parp-1) deficiency could rescue embryonic lethality ofParg−/−mice.Parg−/−Parp-1−/−mice were born viable at a reduced frequency from the expected mendelian ratio in the intercross progeny ofParg+/−Parp-1−/−mice. The results suggest a possibility that the presence of Parp-1 is responsible for the lethality ofParg−/−embryos, and Parg molecules or Parg activity degrading poly(ADP-ribose) might be important for embryogenesis. InParg−/−Parp-1−/−mice, Parg protein was not detected in various tissues, and the protein level ofTimm23, a 5’-upstream gene ofParg, was reduced compared with that inParg+/+Parp-1−/−mice.Parg−/−Parp-1−/−mice showed retarded growth compared withParg+/+Parp-1−/−mice, and died within 3 months of age accompanied with severe renal failure. Glomerular sclerosis, tubular dilatation, and hyaline casts in the kidney were observed inParg−/−Parp-1−/−mice. An increase in blood urea nitrogen (p< 0.05), a marked increase of albumin level in urine (p< 0.01) and its concomitant decrease in serum (p< 0.05) were also detected inParg−/−Parp-1−/−mice compared with theParg+/+Parp-1−/−counterpart. The results imply that the combinedParg and Parp-1loss with a hypomorphic state ofTimm23leads to the development of severe renal failure.