Dataset Information

DIA-Based Proteomic Analysis of Kidney Tissues in Mice with Acetaminophen-Induced Kidney Injury

ABSTRACT: Acetaminophen (APAP) overdose can cause acute kidney injury (AKI), but its molecular mechanisms remain poorly understood and no effective treatments are currently available. In this study, we performed an integrated analysis combining transcriptomic, proteomic, and phosphoproteomic profiling of kidney tissues from APAP-treated mice to investigate the underlying molecular mechanisms and identify potential therapeutic targets. Ten-week-old male C57BL/6 mice were fasted overnight for 16 hours prior to APAP administration. AKI was induced by intraperitoneal injection of a high dose of APAP (300 mg/kg body weight) for 6 hours (n = 4), while control mice received an equivalent volume of PBS via intraperitoneal injection (n = 4). Kidney tissues were collected from both APAP-treated and control groups for downstream omics analyses.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Kidney

DISEASE(S): Acute Kidney Tubular Necrosis

SUBMITTER: Jianxin Zheng

LAB HEAD: Jianxin Zheng

PROVIDER: PXD063122 | Pride | 2025-11-24

REPOSITORIES: Pride

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Publications

A multi-omics landscape of programmed cell death in acetaminophen-induced acute kidney injury.

Zheng Jianxin J Lai Peng P Wu Jiaheng J Li Yuqiu Y Chen Fengxian F Zhu Dong D

Renal failure 20251117 1

Acetaminophen (APAP) overdose is a known cause of acute kidney injury, yet the underlying molecular mechanisms remain incompletely understood. In this study, we conducted integrated transcriptomic, proteomic, and phosphoproteomic analyses of kidney tissues from mice with early-stage APAP-induced nephrotoxicity and corresponding controls. A total of 884 genes related to 13 distinct forms of programmed cell death (PCD)-including alkaliptosis, apoptosis, autophagy, cuproptosis, disulfidptosis, ento ...[more]

PMID: 41249093

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Project description:Renal hypoxia is widespread in acute kidney injury (AKI) of various aetiologies. Hypoxia adaptation, conferred through the hypoxia-inducible factor (HIF), appears to be insufficient. Here we show that HIF activation in renal tubules through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO) protects from rhabdomyolysis-induced AKI. In this model, histological observations indicate that injury mainly affects proximal convoluted tubules, with 5% necrosis at d1 and 40% necrosis at d2. HIF-1alpha up-regulation in distal tubules reflects renal hypoxia. However, lack of HIF in proximal tubules suggests insufficient adaptation by HIF. AKI in VHL-KO mice leads to prominent HIF activation in all nephron segments, as well as to reduced serum creatinine, serum urea, tubular necrosis, and apoptosis marker caspase-3 protein. At d1 after rhabdomyolysis, when tubular injury is potentially reversible, HIF mediated protection in AKI is associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal as demonstrated by qPCR, pathway enrichment analysis and immunohistochemistry. Together, our data provide evidence for a HIF-orchestrated multi-level shift towards glycolysis as a major mechanism for protection against acute tubular injury. All experiments were carried out in transgenic mice in which selective renal tubular VHL knockout (VHL-KO) was inducible by doxycycline (Reference: Mathia S, Paliege A, Koesters R, Peters H, Neumayer HH, Bachmann S, Rosenberger C. Action of hypoxia-inducible factor in liver and kidney from mice with Pax8-rtTA-based deletion of von Hippel-Lindau protein. Acta Physiol (Oxf). 2013; 207(3):565-76.). Four groups of animals were used: 1) controls: untreated mice; 2) VHL-KO: injected with doxycycline (0.1 mg per 10 g body weight SC), 4 days prior to sacrifice; 3) AKI: rhabdomyolysis; 4) VHL-KO/AKI: doxycycline plus rhabdomyolysis. To induce AKI, 50% glycerol (0.05 ml per 10 g body weight) was injected IM into the left hind limb under isoflurane narcosis. Drinking water was withdrawn between 20 h prior and 24 h after glycerol injection.

Project description:Microarray analysis of human kidneys with acute kidney injury (AKI) has been limited because such kidneys are seldom biopsied. However, all kidney transplants experience AKI, and early kidney transplants without rejection are an excellent model for human AKI: they are screened to exclude chronic kidney disease, frequently biopsied, and have extensive follow-up. We used histopathology and microarrays to compare indication biopsies from 28 transplants with AKI to 11 pristine protocol biopsies of stable transplants. Kidneys with AKI showed increased expression of 394 injury-repair response associated transcripts, including many known epithelial injury molecules (e.g. ITGB6, LCN2), tissue remodeling molecules (e.g. VCAN), and inflammation molecules (S100A8, ITGB3). Many other genes also predict the phenotype, depending on statistical filtering rules, including AKI biomarkers as HAVCR1 and IL18. Most mouse orthologs of the top injury-repair transcripts were increased in published mouse AKI models. Pathway analysis of the injury-repair transcripts revealed similarities to cancer, development, and cell movement. The injury-repair transcript score AKI kidneys correlated with reduced function, future recovery, brain death, and need for dialysis, but not future graft loss. In contrast, histologic features of "acute tubular injury" did not correlate with function or with the molecular changes. Thus the injury-repair associated transcripts represent a massive coordinate injury-repair response of kidney parenchyma to AKI, similar to mouse AKI models, and provide an objective measure for assessing the severity of AKI in kidney biopsies and validation for the use of many AKI biomarkers. AKI biopsies sample names and CEL files are from GSE21374. All consenting renal transplant patients undergoing biopsies for cause as standard of care between 09/2004 and 10/2007 at the university of Alberta or between 11/2006 and 02/2007 at the University of Illinois were included in the analysis. In addition to the cores required for standard histopathology, we collected one core for gene expression studies. the relationship between gene expression in the biopsy and subsequent graft loss was analyzed. This dataset is part of the TransQST collection.

			Action	DRS
	DIA_result.csv	Csv
	WT_0h_1.raw	Raw
	WT_0h_2.raw	Raw
	WT_0h_3.raw	Raw
	WT_0h_4.raw	Raw