Tubular STAT3 Limits Renal Inflammation in Autosomal Dominant Polycystic Kidney Disease

纤毛 包装D1 常染色体显性多囊肾病 多囊肾病 炎症 生物 促炎细胞因子 细胞生物学 旁分泌信号 免疫系统 车站3 免疫学 信号转导 内分泌学 遗传学 受体
作者
Martine Burtin,Maroua Baaziz,Amandine Aka,Mohammad Mazloum‐Ardakani,Clément Nguyen,E. Wolfgang Kuehn,Gerd Walz,Frank Bienaimé
出处
期刊:Journal of The American Society of Nephrology 卷期号:31 (5): 1035-1049 被引量:13
标识
DOI:10.1681/asn.2019090959
摘要

Significance Statement Recent research into the pathophysiology of autosomal dominant polycystic kidney disease indicates that both signaling of primary cilia of tubular cells and immune cell infiltration play key roles. However, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, an important modulator of inflammatory response and a cilia component, is activated in polycystin 1 (PKD1)–deficient tubular cells and is suspected to promote cyst growth. In this work, the authors used murine models involving postdevelopmental ablation of Pkd1 , Stat3 , and cilia to assess STAT3’s role in the disease. They found that, contrary to previous assumptions, STAT3 does not appear to be a critical mediator of cyst growth, but instead acts in a feedback loop that restricts cilia-dependent renal inflammation by repressing proinflammatory cytokines. Background The inactivation of the ciliary proteins polycystin 1 or polycystin 2 leads to autosomal dominant polycystic kidney disease (ADPKD). Although signaling by primary cilia and interstitial inflammation both play a critical role in the disease, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, a component of the cilia proteome that is involved in crosstalk between immune and nonimmune cells in various tissues, has been suggested as a factor fueling ADPKD progression. Method To explore how STAT3 intersects with cilia signaling, renal inflammation, and cyst growth, we used conditional murine models involving postdevelopmental ablation of Pkd1 , Stat3 , and cilia, as well as cultures of cilia-deficient or STAT3-deficient tubular cell lines. Results Our findings indicate that, although primary cilia directly modulate STAT3 activation in vitro , the bulk of STAT3 activation in polycystic kidneys occurs through an indirect mechanism in which primary cilia trigger macrophage recruitment to the kidney, which in turn promotes Stat3 activation. Surprisingly, although inactivating Stat3 in Pkd1 -deficient tubules slightly reduced cyst burden, it resulted in a massive infiltration of the cystic kidneys by macrophages and T cells, precluding any improvement of kidney function. We also found that Stat3 inactivation led to increased expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells. Conclusions STAT3 appears to repress the expression of proinflammatory cytokines and restrict immune cell infiltration in ADPKD. Our findings suggest that STAT3 is not a critical driver of cyst growth in ADPKD but rather plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
量子星尘发布了新的文献求助10
1秒前
1秒前
Jonathan完成签到,获得积分10
5秒前
wsj发布了新的文献求助10
6秒前
7秒前
整齐小松鼠应助wsj采纳,获得10
11秒前
11秒前
12秒前
12秒前
15秒前
15秒前
15秒前
16秒前
Owen应助超速也文章采纳,获得10
17秒前
张雯思发布了新的文献求助10
19秒前
清爽尔安发布了新的文献求助10
19秒前
20秒前
孙燕应助幸福大白采纳,获得30
20秒前
香香应助研友_Zzrx6Z采纳,获得10
20秒前
22秒前
23秒前
23秒前
从容的柜子完成签到 ,获得积分10
24秒前
24秒前
木可发布了新的文献求助10
25秒前
清爽尔安完成签到,获得积分10
26秒前
Komorebi完成签到 ,获得积分10
26秒前
qqq发布了新的文献求助10
26秒前
所所应助独特乘云采纳,获得10
27秒前
28秒前
29秒前
小蘑菇应助发疯的草莓采纳,获得10
30秒前
小绵羊发布了新的文献求助10
31秒前
八卦巧克力完成签到,获得积分10
31秒前
lzw发布了新的文献求助10
32秒前
iNk应助wodetaiyangLLL采纳,获得10
35秒前
36秒前
帆帆完成签到,获得积分10
36秒前
38秒前
40秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3989406
求助须知:如何正确求助?哪些是违规求助? 3531522
关于积分的说明 11254187
捐赠科研通 3270174
什么是DOI,文献DOI怎么找? 1804901
邀请新用户注册赠送积分活动 882105
科研通“疑难数据库(出版商)”最低求助积分说明 809174