Department of Pathology and
Department of Pathology and.
J Am Soc Nephrol. 2019 Sep;30(9):1641-1658. doi: 10.1681/ASN.2018111143. Epub 2019 Aug 12.
GATA3 is a dual-zinc finger transcription factor that regulates gene expression in many developing tissues. In the kidney, GATA3 is essential for ureteric bud branching, and mice without it fail to develop kidneys. In humans, autosomal dominant mutations can cause renal aplasia as part of the hypoparathyroidism, renal dysplasia, deafness (HDR) syndrome that includes mesangioproliferative GN. This suggests that GATA3 may have a previously unrecognized role in glomerular development or injury.
To determine GATA3's role in glomerular development or injury, we assessed GATA3 expression in developing and mature kidneys from heterozygous (/-) knockout mice, as well as injured human and rodent kidneys.
We show that GATA3 is expressed by FOXD1 lineage stromal progenitor cells, and a subset of these cells mature into mesangial cells (MCs) that continue to express GATA3 in adult kidneys. In mice, we uncover that GATA3 is essential for normal glomerular development, and mice with haploinsufficiency of have too few MC precursors and glomerular abnormalities. Expression of GATA3 is maintained in MCs of adult kidneys and is markedly increased in rodent models of mesangioproliferative GN and in IgA nephropathy, suggesting that GATA3 plays a critical role in the maintenance of glomerular homeostasis.
These results provide new insights on the role GATA3 plays in MC development and response to injury. It also shows that GATA3 may be a novel and robust nuclear marker for identifying MCs in tissue sections.
GATA3 是一种双锌指转录因子，可调节许多组织的基因表达。在肾脏中，GATA3 对于输尿管芽分支至关重要，缺乏它的小鼠无法发育出肾脏。在人类中，常染色体显性突变可导致肾发育不全，作为包括系膜增生性肾小球肾炎的甲状旁腺功能减退、肾发育不全、耳聋（HDR）综合征的一部分。这表明 GATA3 可能在肾小球发育或损伤中具有以前未被认识到的作用。
为了确定 GATA3 在肾小球发育或损伤中的作用，我们评估了杂合子（/-）敲除小鼠的发育和成熟肾脏以及损伤的人类和啮齿动物肾脏中的 GATA3 表达。
我们表明 GATA3 由 FOXD1 谱系基质祖细胞表达，其中一些细胞成熟为系膜细胞（MC），在成年肾脏中继续表达 GATA3。在小鼠中，我们发现 GATA3 对于正常肾小球发育至关重要，并且杂合不足的小鼠 MC 前体过少且肾小球异常。GATA3 在成年肾脏的 MC 中表达得到维持，并且在系膜增生性肾小球肾炎和 IgA 肾病的啮齿动物模型中显著增加，这表明 GATA3 在维持肾小球稳态中起着关键作用。
这些结果为 GATA3 在 MC 发育和对损伤的反应中所起的作用提供了新的见解。它还表明 GATA3 可能是鉴定组织切片中 MC 的新的、稳健的核标记物。
