Department of Urology, Genetics, and Devlopment, Pathology and Cell Biology and CSCI, Columbia University, New York, NY, 10032, USA.
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
Nat Commun. 2019 Oct 9;10(1):4589. doi: 10.1038/s41467-019-12332-0.
The urothelium is an epithelial barrier lining the bladder that protects against infection, fluid exchange and damage from toxins. The nuclear receptor Pparg promotes urothelial differentiation in vitro, and Pparg mutations are associated with bladder cancer. However, the function of Pparg in the healthy urothelium is unknown. Here we show that Pparg is critical in urothelial cells for mitochondrial biogenesis, cellular differentiation and regulation of inflammation in response to urinary tract infection (UTI). Superficial cells, which are critical for maintaining the urothelial barrier, fail to mature in Pparg mutants and basal cells undergo squamous-like differentiation. Pparg mutants display persistent inflammation after UTI, and Nf-KB, which is transiently activated in response to infection in the wild type urothelium, persists for months. Our observations suggest that in addition to its known roles in adipogegnesis and macrophage differentiation, that Pparg-dependent transcription plays a role in the urothelium controlling mitochondrial function development and regeneration.
尿路上皮是一种覆盖在膀胱表面的上皮屏障，可防止感染、液体交换和毒素损伤。核受体 Pparg 可促进体外尿路上皮分化，而 Pparg 突变与膀胱癌有关。然而，Pparg 在健康尿路上皮中的功能尚不清楚。本文中我们发现，Pparg 对尿路上皮细胞中的线粒体生物发生、细胞分化和尿路感染（UTI）反应中的炎症调节至关重要。浅层细胞对于维持尿路上皮屏障至关重要，而 Pparg 突变体中这些细胞无法成熟，基底细胞则发生鳞状样分化。UTI 后，Pparg 突变体持续存在炎症，而 NF-κB 在野生型尿路上皮中对感染的反应是短暂激活的，但其在 Pparg 突变体中持续数月。我们的观察结果表明，除了已知在脂肪生成和巨噬细胞分化中的作用外，Pparg 依赖性转录在控制尿路上皮中线粒体功能发育和再生中也发挥作用。
