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Proteomics and phosphoprotemics analysis of Ndufs4 KO and wild-type mouse brain upon rapamycin treatment

ABSTRACT: + 2 experiments: - effect of rapamycin in Ndufs4 KO mouse --> 3 groups: WT, KO and KR (KO+RP) - effect of rapamycin in wild-type mouse --> 2 groups: WT and WR (WT+RP) + samples from whole brains homogenized in liquid nitrogen + proteins digested with trypsin. No fractionation + phosphopeptides enriched with IMAC beads + instruments: Orbitrap Q Exactive (for proteome), Orbitrap LTQ Velos (for phosphoproteome) + 90 minutes gradient runs + search and quantification with MaxQuant

INSTRUMENT(S): LTQ Orbitrap Velos, Q Exactive

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Judit Villen

PROVIDER: MSV000083273 | MassIVE | Fri Dec 21 07:15:00 GMT 2018

SECONDARY ACCESSION(S): PXD012158

REPOSITORIES: MassIVE

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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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Proteomics and phosphoprotemics analysis of Ndufs4 KO and wild-type mouse brain upon rapamycin treatment

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