Dataset Information

FAM3A plays a key role in protecting against tubular cell pyroptosis and acute kidney injury through PI3K/AKT/NRF2-dependent pathway

ABSTRACT: Acute kidney injury (AKI) is in a high prevalence worldwide, but there is no therapeutic strategies nowadays. Renal tubular cell death plays a key role in the initiation and progression of AKI. However, the underlying mechanisms have not been elucidated. In this study, we found that tubular cell pyroptosis was primarily responsible to AKI progression, which is highly related with ATP depletion. FAM3A is a mitochondrial protein responsible for ATP synthesis. Herein, we found that FAM3A was decreased in AKI mice, especially in those pyroptotic tubular cells. FAM3A also decreased in clinical patients with AKI, and negatively correlated with inflammation and tubular cell injury. Gene ablation of FAM3A strongly induced NLRP3 inflammasome, Caspase-1, GSDMD, IL-1β, and IL-18, the pyroptotic markers in tubular epithelial cells, as well as triggered inflammation and mitochondrial dysfunction. Conversely, overexpression of FAM3A greatly ameliorated pyroptosis and inflammation, and reversed fatty-acid oxidation function in tubular cells. Mechanically, FAM3A activated PI3K/AKT/NRF2 pathway, which improved mitochondrial dysfunction and prevented cell pyroptosis. To activate NRF2 could strongly inhibit tubular cell pyroptosis, inflammation, mitochondrial dysfunction, and renal function decline in FAM3A knockout mice. Hence, our study provides the new mechanisms for AKI progression. We also demonstrated that FAM3A is a potential therapeutic target for treating AKI.

ORGANISM(S): Mus musculus

PROVIDER: GSE235903 | GEO | 2025/06/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Hypertension and persistent activation of the renin-angiotensin system (RAS) are predisposing factors for development of acute kidney injury (AKI). Although bone marrow-derived stromal cells (BMSCs) have shown therapeutic promise in treatment of AKI, the impact of pathological RAS on BMSC functionality has remained unresolved. RAS and its local components in the bone marrow are involved in several key steps of cell maturation processes. This may also render BMSC population vulnerable to alterations even in the early phases of RAS pathology. We isolated TG-BMSCs from young, end organ disease-free rats with increased RAS activation (human angiotensinogen/renin double transgenic rats; dTGR) that eventually develop hypertension and die of end-organ damage and kidney failure at 8-weeks-of-age. Control cells were isolated from wild-type Sprague-Dawley rats (SD-BMSCs). Cell phenotype, mitochondrial reactive oxygen species (ROS) production and respiration were assessed, and gene expression profiling was carried out using microarrays. Cells’ therapeutic efficacy was evaluated in a rat model of acute ischemia-reperfusion-induced AKI. Serum urea and creatinine were measured at 24h and 48h. Acute tubular damage was scored and immunohistochemistry was used for evaluation for markers of inflammation (MCP-1, ED-1), and kidney injury (KIM-1, NGAL). TG-BMSCs showed distinct mitochondrial morphology, decreased cell respiration, and increased production of ROS. Gene expression profiling revealed a pronounced pro-inflammatory phenotype. In contrast to the therapeutic effect of SD-BMSCs, administration of TG-BMSCs in the AKI model resulted in exacerbation of kidney injury and high mortality. Our results demonstrate that early persistent RAS activation can dramatically compromise therapeutic potential of BMSCs by shift into a pro-inflammatory phenotype with mitochondrial dysfunction. A comparison of transcriptome of a bone marrow-derived stromal cells from a double-transgene rats compared to those from control rats

Project description:Sepsis is a severe and dysregulated inflammatory disease that often precedes the development of acute kidney injury (AKI) with consequent worsening outcome. The main characteristics of sepsis-induced AKI include endothelial cell (EC) dysfunction, infiltration of inflammatory cells, glomerular thrombosis, and renal tubular epithelial cells (RTEC) injury. Numerous studies have demonstrated that mammalian target of rapamycin (mTOR) activation has been implicated in the initiation and progression of renal injury in course of sepsis. However, little is known, about the molecular basis of mTOR role in EC and RTEC dysfunction. Here, we evaluate whether mTOR inhibition by Rapamycin (Rp) as potential strategy to ameliorate renal function and dissected the molecular mechanisms involved. In a mouse model of lipopolysaccharide (LPS)-induced AKI , LPS injection led to a time-dependent increase of serum creatinine and significant morphological changes in renal parenchyma associated with increased collagen deposits and endothelial dysfunction. Interestingly, Rp treatment significantly decreased creatine levels and preserved renal parenchyma, counteracting Endothelial-to mesenchymal transition (EndMT) process and early fibrosis through the inhibition of ERK pathway. Next, we examined the effects of LPS-TLR4 interaction in RTECs. Through a whole-genome DNA methylation analysis in cultured RTEC, we found that LPS induced aberrant methylation, particularly in regions involved in premature aging. The most represented genes were CD39 and WFS1. LPS stimulation of RTEC led to up-regulation of SA-β Gal and cell cycle arrest markers such as p21. In accordance, in endotoxemic mice, we found a decreased expression of CD39 concurrent with Klotho down-regulation. Administration of Rp exerted anti-aging effects in endotoxemic mice, preserving CD39 and Klotho expression. In conclusion, we demonstrated that mTOR inhibition could offer novel strategies to protect endothelial and tubular compartment from accelerated aging and fibrosis thus counteracting the progression to chronic kidney disease.

Project description:Background. Many age-associated disorders (including diabetes, cancer, and neurodegenerative diseases) have been linked to mitochondrial dysfunction, which leads to impaired cellular bioenegetics (decreased ATP production) and increased oxidative stress. However, it is not known what genetic and molecular pathways underlie differential vulnerability to mitochondrial dysfunction observed among different cell types. Methodology/Principal Findings. Starting with CRI-G1 insulinoma cells as a model of a neuronal/endocrine cell type, we isolated a novel (CRI-G1-RS) cell line that was more susceptible to cell death induced by mitochondrial respiratory chain inhibitors or direct oxidants than the parental CRI-G1 cell line (for clarity renamed CRI-G1-RR). In contrast, RS cells were equally vulnerable to mitochondrial uncoupling and less vulnerable to protein kinase inhibition than RR cells, suggesting that differences in vulnerability to mitochondrial toxins among the two cell types did not stem from differences in ATP production/utilization or in downstream apoptotic machinery. Genome-wide gene expression analysis and follow-up biochemical studies revealed that, in this experimental system, increased vulnerability to mitochondrial and oxidative stress was associated with (1) inhibition of ARE/Nrf2/Keap1 antioxidant pathway; (2) decreased expression of antioxidant and phase I/II conjugation enzymes, most of which are Nrf2 transcriptional targets; (3) increased expression of molecular chaperones, many of which are also considered Nrf2 transcriptional targets; and (4) increased expression of β cell-specific genes and transcription factors that specify/maintain β cell fate. Conclusions/Significance. The molecular profile presented here will enable identification of individual genes and/or gene clusters that shape vulnerability to mitochondrial dysfunction and thus represent potential therapeutic targets for diabetes and neurodegenerative diseases. In addition, the newly identified CRI-G1-RS cell line represents a new experimental model for investigating how endogenous antioxidants affect glucose sensing and insulin release by pancreatic β cells. Six biological replicates for each of two cell types (12 samples total)

Dataset Information

FAM3A plays a key role in protecting against tubular cell pyroptosis and acute kidney injury through PI3K/AKT/NRF2-dependent pathway

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets