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Proteomics coupled transcriptomics reveals Slc34a1 and Slc34a3 downregulation as potential features of nephrotoxin-induced acute kidney injury

ABSTRACT: Acute kidney injury (AKI) is a clinically common and severe disease with a significant economic burden worldwide. Although several studies have focused on the pathogenesis of AKI, much remains unknown about its complex molecular regulatory network and pathophysiological mechanisms. This study combines mass spectrometry and RNA sequencing technologies to investigate nephrotoxin-induced AKI mice's protein and RNA expression profiles. The results revealed that Slc34a1 and Slc34a3 were significantly down-regulated in nephrotoxin-induced AKI mice and may be potential diagnostic and therapeutic targets.

ORGANISM(S): Mus Musculus

SUBMITTER: jiangbei Yuan

PROVIDER: PXD044372 | iProX | Thu Aug 03 00:00:00 BST 2023

REPOSITORIES: iProX

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Proteomics coupled transcriptomics reveals Slc34a1 and Slc34a3 downregulation as potential features of nephrotoxin-induced acute kidney injury

Project description:Acute kidney injury (AKI) is a clinically common and severe disease with a significant economic burden worldwide. Although several studies have focused on the pathogenesis of AKI, much remains unknown about its complex molecular regulatory network and pathophysiological mechanisms. This study combines mass spectrometry and RNA sequencing technologies to investigate nephrotoxin-induced AKI mice's protein and RNA expression profiles. The results revealed that Slc34a1 and Slc34a3 were significantly down-regulated in nephrotoxin-induced AKI mice and may be potential diagnostic and therapeutic targets.

2023-08-11 | GSE240304 | GEO

Proteomic analysis of septic renal acute phase response

Project description:Sepsis-induced acute kidney injury (AKI) is the most common form of AKI with poor outcomes. Renal proteomic analysis after bacterial lipopolysaccharide (LPS) administration revealed that the local renal acute phase reaction (APR) is one of the strongest responses of the kidney during septic AKI in mice. Evaluation of mRNA expression confirmed that most acute phase proteins were produced in the kidney. Our study also provides missing information on the time course of septic renal APR. Proteomic analysis of LPS-induced AKI demonstrated a marked upregulation of local renal acute phase response (APR) that commenced a few hours post injection and peaked at 24 h. Much more APPs were involved in the renal APR than previously identified.

2020-01-08 | PXD014664 | Pride

Human Cortical Kidney Sections

Project description:Acute kidney injury (AKI) is a major health burden in the United States. Macrophages have been shown to mediate AKI in murine models. Murine kidneys contain multiple subpopulations of kidney resident macrophages (KRM) that are transcriptionally and spatially distinct. We hypothesized the human kidney contains orthologous KRM subpopulations, both transcriptionally and spatially. We utilized kidney sections from donors diagnosed with mild to moderate AKI in order to increase the translatability of murine research to clinical settings.

2024-03-31 | GSE228169 | GEO

Role of miRNAs in acute kidney injury recovery induced by mesenchymal stromal cells and derived extracellular vesicles.

Project description:Phenotypic changes induced by extracellular vesicles (EVs) have been implicated in the recovery of acute kidney injury (AKI) induced by mesenchymal stromal cells (MSCs). miRNAs are potential candidates for cell reprogramming towards a pro-regenerative phenotype. The aim of the present study was to evaluate whether miRNA de-regulation inhibits the regenerative potential of MSCs and derived-EVs in a model of glycerol-induced AKI in SCID mice. For this purpose, we generated MSCs depleted of Drosha, a critical enzyme of miRNA maturation, to alter miRNA expression within MSCs and EVs. Drosha knock-down MSCs (MSC-Dsh) maintained the phenotype and differentiation capacity. They produced EVs that did not differ from those of wild type cells in quantity, surface molecule expression and internalization within renal tubular epithelial cells. However, EVs derived from MSC-Dsh (EV-Dsh) showed global down-regulation of miRNAs. Whereas, wild type MSCs and derived EVs were able to induce morphological and functional recovery in AKI, MSC-Dsh and EV-Dsh were ineffective. RNA sequencing analysis showed that genes deregulated in the kidney of AKI mice were restored by treatment with MSCs and EVs but not by MSC-Dsh and EV-Dsh. Gene Ontology analysis showed that down-regulated genes in AKI were associated with fatty acid metabolism. The up-regulated genes in AKI were involved in inflammation, ECM-receptor interaction and cell adhesion molecules. These alterations were reverted by treatment with wild type MSCs and EVs, but not by the Drosha counterparts. In conclusion, miRNA depletion in MSCs and EVs significantly reduced their intrinsic regenerative potential in AKI, suggesting a critical role of miRNAs. RNA-seq

2015-05-07 | E-GEOD-59958 | biostudies-arrayexpress

The contribution of RNA oxidation to acute kidney injury: evidence from ISG20-mediated oxidized RNA degradation

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2020-07-03 | E-MTAB-8133 | biostudies-arrayexpress

Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury

Project description:Background: Acute kidney injury (AKI) occurs frequently in critically ill patients and is associated with adverse outcomes. Cellular mechanisms underlying AKI and kidney cell responses to injury remain incompletely understood. Methods: We performed single-nuclei transcriptomics, bulk transcriptomics, molecular imaging studies, and conventional histology on kidney tissues from 8 individuals with severe AKI (stage 2 or 3 according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria). Specimens were obtained within 1-2 hours after individuals had succumbed to critical illness associated with respiratory infections, with 4 of 8 individuals diagnosed with COVID-19. Control kidney tissues were obtained post-mortem or after nephrectomy from individuals without AKI. Results: High-depth single cell-resolved gene expression data of human kidneys affected by AKI revealed enrichment of novel injury-associated cell states within the major cell types of the tubular epithelium, in particular in proximal tubules, thick ascending limbs and distal convoluted tubules. Four distinct, hierarchically interconnected injured cell states were distinguishable and characterized by transcriptome patterns associated with oxidative stress, hypoxia, interferon response, and epithelial-to-mesenchymal transition, respectively. Transcriptome differences between individuals with AKI were driven primarily by the cell type-specific abundance of these four injury subtypes rather than by private molecular responses. AKI-associated changes in gene expression between individuals with and without COVID-19 were similar. Conclusions: The study provides an extensive resource of the cell type-specific transcriptomic responses associated with critical illness-associated AKI in humans, highlighting recurrent disease-associated signatures and inter-individual heterogeneity. Personalized molecular disease assessment in human AKI may foster the development of tailored therapies.

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Project description:Treatment for acute kidney injury (AKI) is suboptimal. A better understanding of its pathogenesis may lead to new therapeutic approaches. Kidney transcriptomics analyses of murine folic acid-induced AKI (FA-AKI) identified Runx1 as the most upregulated RUNX family gene. RUNX1 overexpression in FA-AKI was validated at the mRNA and protein levels and localized mainly to tubular cell nuclei. Bacterial lipopolysaccharide (LPS)-induced cytokine storm-AKI also upregulated kidney RUNX1. Increased tubular and interstitial RUNX1 expression were also observed in human AKI. In cultured murine tubular cells, the proinflammatory cytokine TWEAK and LPS increased RUNX1 and IL-6 expression. Mechanistically, RUNX1 bound to the Il-6 gene promoter while RUNX1 targeting with either the chemical inhibitor Ro5-3335 or a specific small interfering RNA (siRNA) prevented the TWEAK- and LPS-induced upregulation of IL-6 through a RUNX1/NFκB p50 pathway. TWEAK and LPS also induced RUNX1 binding to the promoter of Cdkn1a which encodes the cyclin-dependent kinase inhibitor p21 and increased p21 expression. In vivo, preventive Ro5-3335 improved kidney function and reduced inflammation and p21 expression in both FA-AKI, and in cytokine storm-AKI. However, administration of Ro5-3335 after the insult only improved kidney function in cytokine storm-AKI. Kidney transcriptomics identified inflammatory genes and the transcription factor Yap1 as key targets of Ro5-3335 in cytokine storm-AKI. In conclusion, RUNX1 contributes to AKI by driving the expression of genes involved in inflammation and represents a novel therapeutic target in AKI.

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Proteomic analysis of cisplatin exposure on the kidney cortex proteome and the effect of preconditioning

Project description:Acute kidney injury and nephrotoxicity are important clinical side effects of cisplatin. Thus, the mechanisms of this disease, and potential treatment options are important to understand in their entity. Here, we analyzed the proteome of cisplatin induced acute kidney injury in a mouse model. Functionally we found that calorie restriction was able to completely blunt Cisplatin induced AKI, and hypoxia ameliorated cCisplatin induced AKI. To investigate the mechanism for this in high throughput, we performed label-free single-shot proteomic analyses of these kidneys.Acute kidney injury and nephrotoxicity are important clinical side effects of cisplatin. Thus, the mechanisms of this disease, and potential treatment options are important to understand in their entity. Here, we analyzed the proteome of cisplatin induced acute kidney injury in a mouse model. Functionally we found that calorie restriction was able to completely blunt Cisplatin induced AKI, and hypoxia ameliorated cCisplatin induced AKI. To investigate the mechanism for this in high throughput, we performed label-free single-shot proteomic analyses of these kidneys.

2020-01-30 | PXD005525 | Pride

Microarray-based clustering analysis of miRNAs altered in IRI-AKI mouse kidney

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2021-05-14 | GSE172039 | GEO

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