#1914 Comprehensive single-cell sequencing and lipidomics identify diverse injury states and cholesterol dynamics of the PTs in AKI-to-CKD transition

脂类学 过渡(遗传学) 动力学(音乐) 计算生物学 医学 化学 生物信息学 生物 生物化学 心理学 基因 教育学
作者
Yilin Zhang,Lin‐Li Lv,Bi‐Cheng Liu
出处
期刊:Nephrology Dialysis Transplantation [Oxford University Press]
卷期号:39 (Supplement_1)
标识
DOI:10.1093/ndt/gfae069.001
摘要

Abstract Background and Aims The underlying cellular events and metabolic dysfunction of acute kidney injury (AKI) transformed to chronic kidney disease (CKD) is still largely unclear. Previous studies have suggested lipids and metabolites have a profound impact on acute and chronic inflammation. One of the main sites of renal lipid accumulation is the proximal tubule cells (PTs). Here we demonstrated the injury states and cholesterol dynamics of PTs and its potential function in AKI to CKD in unilateral ischemia-reperfusion injury (UIR) mice model. Method We employed single-cell combinatorial indexing lipidomics to analyze 15 mouse kidneys from a mouse model of failed repaired UIR at five time points. We identified cell types through unsupervised clustering analysis. Differential gene expression, enrichment analysis and main function scoring were applied to define functional heterogeneity and injury states of PTs. Next, pseudotime analysis of differentiation transitions was performed to create the diverse PT lineages. Finally, using SCENIC analysis, we identified the key transcription factors that drive the differentiation of PTs. Results We identified 13 main cell clusters and the dynamic changes in the process of AKI to CKD transition were analysed. A remarkable decrease in PTs after injury at day 1 followed with a recovery at day 3 post AKI were observed. Spatiotemporal profiling of the main cell types showed that the most injured areas in the acute stages of kidney injury are primarily concentrated in the outer stripe, specifically the region where the proximal straight tubules (PSTs) are located. In order to gain a higher resolution of the dynamics of PST subtypes during AKI to CKD, we performed sub-clustering analysis specifically on PSTs, partitioning them into 10 subclusters. Single-cell analysis identified maladaptive PSTs (PST-5) with the highest apoptosis and ferroptosis scores. Notably, pseudotime analysis revealed that PST-5 differentiated from PST-4, which has the highest lipid metabolism score. Indeed, among all the cells in the kidney, the PTs exhibited the most active metabolic reprogramming due to their differentiation and redifferentiation early after AKI. Lipid omics profiling reveals an abnormal elevation of the cholesterol metabolites 27-hydroxycholesterol (27-OH) and 25-hydroxycholesterol (25-OH) following AKI. Interestingly, the PST-4-specific expression of Cyp7b1 served as a key enzyme regulating the concentration of 27-OH. This gene has been found to be significantly absent after AKI. Moreover, the binding of 27HC, a natural ligand, to endogenous estrogen receptor alpha (ERα) leads to the upregulation of heme oxygenase 1 (Hmox1), thereby promoting ferroptosis. Finally, SCENIC analysis revealed that Cyp7b1-mediated accumulation of 27-HC is dependent on the transcription factor Atf3. Conclusion Our results indicate that Cyp7b1 deficiency confers ferroptosis, which are primarily dependent on the upregulation of cellular cholesterol homeostasis and 27-HC secretion, leading to the progression of AKI. These findings suggest that the Cyp7b1/Hmox1/Atf3/27-HC axis may serve as a potential therapeutic target for preventing the development of CKD.

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

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
张先生2365完成签到,获得积分10
1秒前
傲娇幼丝发布了新的文献求助10
1秒前
晶米发布了新的文献求助10
2秒前
小写发布了新的文献求助30
4秒前
畅小畅完成签到,获得积分20
6秒前
6秒前
平常的可乐完成签到 ,获得积分10
9秒前
文先生完成签到,获得积分10
10秒前
爱科研的八哥完成签到,获得积分10
11秒前
ZHOU发布了新的文献求助10
12秒前
Solaris发布了新的文献求助30
12秒前
14秒前
14秒前
爆米花应助LiAlan采纳,获得10
15秒前
研友_VZG7GZ应助知其荣采纳,获得10
15秒前
17秒前
上官若男应助LP采纳,获得10
18秒前
18秒前
wjh发布了新的文献求助10
19秒前
Woo_SH完成签到 ,获得积分10
19秒前
19秒前
19秒前
呦呦发布了新的文献求助10
20秒前
21秒前
baifeng发布了新的文献求助10
22秒前
23秒前
23秒前
24秒前
受伤飞丹完成签到,获得积分10
24秒前
黑暗系完成签到,获得积分10
25秒前
27秒前
吃猫的鱼发布了新的文献求助30
27秒前
受伤飞丹发布了新的文献求助10
28秒前
amber发布了新的文献求助10
29秒前
29秒前
29秒前
传奇3应助oubggggggg采纳,获得10
29秒前
朝暮星河完成签到,获得积分10
30秒前
31秒前
LP发布了新的文献求助10
31秒前
高分求助中
Sustainability in Tides Chemistry 2000
The ACS Guide to Scholarly Communication 2000
Studien zur Ideengeschichte der Gesetzgebung 1000
TM 5-855-1(Fundamentals of protective design for conventional weapons) 1000
Threaded Harmony: A Sustainable Approach to Fashion 810
Pharmacogenomics: Applications to Patient Care, Third Edition 800
Gerard de Lairesse : an artist between stage and studio 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 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 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3076162
求助须知:如何正确求助?哪些是违规求助? 2729044
关于积分的说明 7507177
捐赠科研通 2377267
什么是DOI,文献DOI怎么找? 1260526
科研通“疑难数据库(出版商)”最低求助积分说明 611000
版权声明 597164