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Single-cell transcriptome analysis revealed cellular reprogramming following Tetramethylpyrazine treatment in LPS-induced acute lung injury

ABSTRACT: Single-cell transcriptome analysis revealed cellular reprogramming following Tetramethylpyrazine treatment in LPS-induced acute lung injury

PROVIDER: PRJNA1158678 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30599515_1.fastq.gz	Fastqsanger.gz
	SRR30599515_2.fastq.gz	Fastqsanger.gz
	SRR30599516_1.fastq.gz	Fastqsanger.gz
	SRR30599516_2.fastq.gz	Fastqsanger.gz
	SRR30599517_1.fastq.gz	Fastqsanger.gz

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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.

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Single-cell transcriptome analysis revealed cellular reprogramming following Tetramethylpyrazine treatment in LPS-induced acute lung injury

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