人类近端肾小管上皮细胞白细胞介素-1受体信号传导在缺氧性肾损伤期间引发G2/M期阻滞和细胞衰老。

Human proximal tubular epithelial cell interleukin-1 receptor signalling triggers G2/M arrest and cellular senescence during hypoxic kidney injury.

作者信息

Giuliani Kurt T K, Nag Purba, Adams Benjamin C, Wang Xiangju, Hong Seokchan, Grivei Anca, Johnston Rebecca L, Waddell Nicola, Ho Kenneth K C, Tian Yilin, Khan Muhammad Ali, Kim Chang Seong, Ng Monica S Y, Gobe Glenda, Ungerer Jacobus P J, Forbes Josephine M, Healy Helen G, Kassianos Andrew J

机构信息

Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Brisbane, QLD, Australia.

Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.

出版信息

Cell Death Dis. 2025 Jan 31;16(1):61. doi: 10.1038/s41419-025-07386-6.

DOI:10.1038/s41419-025-07386-6

PMID:39890773

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11785723/

Abstract

Hypoxia and interleukin (IL)-1β are independent mediators of tubulointerstitial fibrosis, the histological hallmark of chronic kidney disease (CKD). Here, we examine how hypoxia and IL-1β act in synergy to augment maladaptive proximal tubular epithelial cell (PTEC) repair in human CKD. Ex vivo patient-derived PTECs were cultured under normoxic (21% O) or hypoxic (1% O) conditions in the absence or presence of IL-1β and examined for maladaptive repair signatures. Hypoxic PTECs incubated with IL-1β displayed a discrete transcriptomic profile distinct from PTECs cultured under hypoxia alone, IL-1β alone or under normoxia. Hypoxia+IL-1β-treated PTECs had 692 'unique' differentially expressed genes (DEGs) compared to normoxic PTECs, with 'cell cycle' the most significantly enriched KEGG pathway based on 'unique' down-regulated DEGs (including CCNA2, CCNB1 and CCNB2). Hypoxia+IL-1β-treated PTECs displayed signatures of cellular senescence, with reduced proliferation, G2/M cell cycle arrest, increased p21 expression, elevated senescence-associated β-galactosidase (SA-β-gal) activity and increased production of pro-inflammatory/fibrotic senescence-associated secretory phenotype (SASP) factors compared to normoxic conditions. Treatment of Hypoxia+IL-1β-treated PTECs with either a type I IL-1 receptor (IL-1RI) neutralizing antibody or a senolytic drug combination, quercetin+dasatinib, attenuated senescent cell burden. In vitro findings were validated in human CKD bio-specimens (kidney tissue, urine), with elevated PTEC IL-1RI expression and senescence (SA-β-gal activity) detected in fibrotic kidneys and numbers of senescent (SA-β-gal) urinary PTECs correlating with urinary IL-1β levels and severity of interstitial fibrosis. Our data identify a mechanism whereby hypoxia in combination with IL-1β/IL-1RI signalling trigger PTEC senescence, providing novel therapeutic and diagnostic check-points for restoring tubular regeneration in human CKD.

摘要

缺氧和白细胞介素（IL）-1β是肾小管间质纤维化的独立介质，而肾小管间质纤维化是慢性肾脏病（CKD）的组织学特征。在此，我们研究缺氧和IL-1β如何协同作用，以增强人类CKD中适应性不良的近端肾小管上皮细胞（PTEC）修复。将患者来源的PTEC在常氧（21% O）或缺氧（1% O）条件下，在不存在或存在IL-1β的情况下进行体外培养，并检测适应性不良修复特征。与单独在缺氧、单独在IL-1β或常氧条件下培养的PTEC相比，与IL-1β一起孵育的缺氧PTEC表现出独特的转录组谱。与常氧PTEC相比，缺氧+IL-1β处理的PTEC有692个“独特”的差异表达基因（DEG），基于“独特”下调的DEG（包括CCNA2、CCNB1和CCNB2），“细胞周期”是最显著富集的KEGG途径。与常氧条件相比，缺氧+IL-1β处理的PTEC表现出细胞衰老特征，增殖减少、G2/M细胞周期停滞、p21表达增加、衰老相关β-半乳糖苷酶（SA-β-gal）活性升高以及促炎/纤维化衰老相关分泌表型（SASP）因子产生增加。用I型IL-1受体（IL-1RI）中和抗体或衰老溶解药物组合槲皮素+达沙替尼处理缺氧+IL-1β处理的PTEC，可减轻衰老细胞负担。体外研究结果在人类CKD生物标本（肾组织、尿液）中得到验证，在纤维化肾脏中检测到PTEC的IL-1RI表达升高和衰老（SA-β-gal活性），衰老（SA-β-gal）尿PTEC数量与尿IL-1β水平和间质纤维化严重程度相关。我们的数据确定了一种机制，即缺氧与IL-1β/IL-1RI信号传导相结合触发PTEC衰老，为恢复人类CKD中的肾小管再生提供了新的治疗和诊断检查点。