Academic Nephrology Unit, Department of Infection, Immunity and Cardiovascular Disease, The Medical School, University of Sheffield, Sheffield, UK.
Academic Nephrology Unit, Department of Infection, Immunity and Cardiovascular Disease, The Medical School, University of Sheffield, Sheffield, UK.
Kidney Int. 2017 Mar;91(3):575-586. doi: 10.1016/j.kint.2016.10.039. Epub 2017 Jan 16.
Autosomal dominant polycystic kidney disease (ADPKD) leads to renal failure. The hallmark of ADPKD is increased epithelial proliferation, which has been proposed to be due to atypical signaling including abnormal JAK-STAT activity. However, the relative contribution of JAK-STAT family members in promoting proliferation in ADPKD is unknown. Here, we present siRNA JAK-STAT-focused screens discovering a previously unknown proliferative role for multiple JAK-STAT components (including STAT1, STAT2, STAT4, STAT5a, and STAT5b). Amongst these, we selected to study the growth hormone/growth hormone receptor/STAT5-axis because of its known role as a regulator of growth in nonrenal tissues. Loss of STAT5 function, facilitated by pharmacological inhibition or siRNAs, significantly reduced proliferation with an associated reduction in cyst growth in vitro. To study whether STAT5 is abnormally activated in vivo, we analyzed its expression using two independent mouse models of ADPKD. STAT5 was nuclear, thus activated, in renal epithelial cyst lining cells in both models. To test whether forced activation of STAT5 can modulate proliferation of renal cells in vivo, irrespective of the Pkd1 status, we overexpressed growth hormone. These mice showed increased STAT5 activity in renal epithelial cells, which correlated with de novo expression of cyclin D1, a STAT5 target gene. Chromatin immunoprecipitation experiments revealed that STAT5 transcriptionally activated cyclin D1 in a growth hormone-dependent fashion, thus providing a mechanism into how STAT5 enhances proliferation. Finally, we provide evidence of elevated serum growth hormone in Pkd1 mutant mice. Thus, the growth hormone/STAT5 signaling axis is a novel therapeutic target in ADPKD.
常染色体显性多囊肾病（ADPKD）可导致肾衰竭。ADPKD 的标志是上皮细胞增殖增加，这被认为是由于包括异常 JAK-STAT 活性在内的非典型信号传导所致。然而，在促进 ADPKD 增殖中 JAK-STAT 家族成员的相对贡献尚不清楚。在这里，我们进行了 JAK-STAT 聚焦的 siRNA 筛选，发现了多个 JAK-STAT 成分（包括 STAT1、STAT2、STAT4、STAT5a 和 STAT5b）的先前未知的增殖作用。在这些成分中，我们选择研究生长激素/生长激素受体/STAT5 轴，因为它在非肾脏组织中作为生长调节剂的已知作用。通过药理学抑制或 siRNA 促进 STAT5 功能丧失，可显著减少增殖，并伴有体外囊肿生长减少。为了研究 STAT5 是否在体内异常激活，我们使用两种独立的 ADPKD 小鼠模型分析其表达。STAT5 在两种模型的肾上皮囊肿衬里细胞中均为核内，因此被激活。为了测试无论 Pkd1 状态如何，STAT5 的强制激活是否可以调节体内肾细胞的增殖，我们过表达了生长激素。这些小鼠表现出肾上皮细胞中 STAT5 活性增加，这与 STAT5 靶基因 cyclin D1 的从头表达相关。染色质免疫沉淀实验表明，STAT5 以生长激素依赖的方式转录激活 cyclin D1，从而为 STAT5 如何增强增殖提供了一种机制。最后，我们提供了 Pkd1 突变小鼠血清生长激素升高的证据。因此，生长激素/STAT5 信号通路是 ADPKD 的一种新的治疗靶点。
