PDF(Pubmed)
Abstract：
Acute kidney injury (AKI) is a common condition that lacks effective treatments. In part, this shortcoming is due to an incomplete understanding of the genetic mechanisms that control pathogenesis and recovery. Identifying the molecular and genetic regulators unique to nephron segments that dictate vulnerability to injury and regenerative potential could lead to new therapeutic targets to treat ischemic kidney injury. Pax2 and Pax8 are homologous transcription factors with overlapping functions that are critical for kidney development and are re-activated in AKI. Here, we examined the role of Pax2 and Pax8 in recovery from ischemic AKI and found them upregulated after severe AKI and correlated with chronic injury. Surprisingly, proximal-tubule-selective deletion of Pax2 and Pax8 resulted in a less severe chronic injury phenotype. This effect was mediated by protection against the acute insult, similar to pre-conditioning. Prior to injury, Pax2 and Pax8 mutant mice develop a unique subpopulation of proximal tubule cells in the S3 segment that displayed features usually seen only in acute or chronic injury. The expression signature of these cells was strongly enriched with genes associated with other mechanisms of protection against ischemic AKI including caloric restriction, hypoxic pre-conditioning, and female sex. Thus, our results identified a novel role for Pax2 and Pax8 in mature proximal tubules that regulates critical genes and pathways involved in both the injury response and protection from ischemic AKI.
摘要：
急性肾损伤(AKI)是缺乏有效治疗的常见病。在某种程度上,这一缺陷是由于对控制发病机制和恢复的遗传机制的理解不完全。确定肾单位片段特有的分子和遗传调节因子,其决定损伤的脆弱性和再生潜能,可能导致治疗缺血性肾损伤的新的治疗靶点。Pax2和Pax8是具有重叠功能的同源转录因子，对肾脏发育至关重要，并在AKI中重新激活。这里,我们研究了Pax2和Pax8在缺血性AKI恢复中的作用,发现它们在严重AKI后上调,并与慢性损伤相关.令人惊讶的是,Pax2和Pax8的近端小管选择性缺失导致较不严重的慢性损伤表型。这种作用是通过对急性损伤的保护来介导的，类似于预处理。受伤前,Pax2和Pax8突变小鼠在S3段中形成了独特的近端小管细胞亚群，其表现出通常仅在急性或慢性损伤中可见的特征。这些细胞的表达特征强烈富含与缺血性AKI的其他保护机制相关的基因，包括热量限制，缺氧预处理,和女性性。因此，我们的研究结果确定了Pax2和Pax8在成熟近端小管中的新作用,它们调节参与缺血性AKI损伤应答和保护的关键基因和通路.
