Kruppel-like factor 4 is a negative regulator of STAT3-induced glomerular epithelial cell proliferation
Kruppel-like factor 4 is a negative regulator of STAT3-induced glomerular epithelial cell proliferation
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DOI：
10.1172/jci.insight.98214
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发表时间：
2018-06-21
期刊：
影响因子：
8
通讯作者：
Mallipattu, Sandeep K.
中科院分区：
文献类型：
--
作者：
Estrada, Chelsea C.;Paladugu, Praharshasai;Mallipattu, Sandeep K.
病理性肾小球上皮细胞（GEC）增生是快速进行性肾小球肾炎（RPGN）和局灶节段性肾小球硬化（FSGS）亚型的特征。尽管在这两种疾病中，初始足细胞损伤导致STAT3信号的激活，但调控机制尚不清楚。在这里，我们发现锌指转录因子Kruppel-like factor 4 （KLF4）的缺失由于STAT3信号失调而增强了RPGN和FSGS中GEC的增殖。我们观察到，在肾毒性血清治疗后，足细胞特异性敲低Klf4 （C57BL/6J）会增加STAT3信号通路，并加剧月牙形成。有趣的是，仅在FVB/N背景下足细胞特异性敲低Klf4就足以激活STAT3信号，导致FSGS伴有毛细血管外增生，以及肾功能衰竭和生存率降低。在培养的足细胞中，KLF4的缺失导致STAT3激活和细胞周期再进入，导致有丝分裂灾难。这触发IL-6释放到上清中，激活了顶叶上皮细胞中的STAT3信号。相反，无论是恢复KLF4表达还是抑制STAT3信号都能提高KLF4敲低足细胞的存活率。最后，与对照组相比，携带RPGN的人肾活检标本显示KLF4表达降低，同时磷酸化stat3表达增加。综上所述，这些结果表明KLF4/STAT3信号在足细胞损伤及其对异常GEC增殖的调节中起重要作用。
Pathologic glomerular epithelial cell (GEC) hyperplasia is characteristic of both rapidly progressive glomerulonephritis (RPGN) and subtypes of focal segmental glomerulosclerosis (FSGS). Although initial podocyte injury resulting in activation of STAT3 signals GEC proliferation in both diseases, mechanisms regulating this are unknown. Here, we show that the loss of Kruppel-like factor 4 (KLF4), a zinc-finger transcription factor, enhances GEC proliferation in both RPGN and FSGS due to dysregulated STAT3 signaling. We observed that podocyte-specific knockdown of Klf4 (C57BL/6J) increased STAT3 signaling and exacerbated crescent formation after nephrotoxic serum treatment. Interestingly, podocyte-specific knockdown of Klf4 in the FVB/N background alone was sufficient to activate STAT3 signaling, resulting in FSGS with extracapillary proliferation, as well as renal failure and reduced survival. In cultured podocytes, loss of KLF4 resulted in STAT3 activation and cell-cycle reentry, leading to mitotic catastrophe. This triggered IL-6 release into the supernatant, which activated STAT3 signaling in parietal epithelial cells. Conversely, either restoration of KLF4 expression or inhibition of STAT3 signaling improved survival in KLF4-knockdown podocytes. Finally, human kidney biopsy specimens with RPGN exhibited reduced KLF4 expression with a concomitant increase in phospho-STAT3 expression as compared with controls. Collectively, these results suggest the essential role of KLF4/STAT3 signaling in podocyte injury and its regulation of aberrant GEC proliferation.