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Renal pharmacokinetic adaptation to cholestasis leads to increased accumulation of nephrotoxic drugs due to ABCC6 downregulation in mice

ABSTRACT: Renal pharmacokinetic adaptation to cholestasis leads to increased accumulation of nephrotoxic drugs due to ABCC6 downregulation in mice

PROVIDER: PRJNA874809 | ENA |

REPOSITORIES: ENA

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Renal pharmacokinetic adaptation to cholestasis leads to increased accumulation of nephrotoxic drugs due to ABCC6 downregulation in mice

Project description:In hepatic dysfunction, renal pharmacokinetic adaptation can be observed, although information on the changes in drug exposure and the interorgan regulation of membrane transporters in kidney in liver diseases is limited. This study aimed to clarify the effects of renal exposure to nephrotoxic drugs during cholestasis induced by bile duct ligation (BDL). Among the 11 nephrotoxic drugs examined, the tissue accumulation of imatinib and cisplatin in kidney slices obtained from mice 2 weeks after BDL operation was higher than that in sham-operated mice. The uptake of imatinib in the kidney slices of BDL mice was slightly higher, whereas its efflux from the slices was largely decreased compared to that in sham-operated mice. Proteomic analysis revealed a reduction in renal expression of the efflux transporter multidrug resistance-associated protein 6 (Mrp6/Abcc6) in BDL mice, and both imatinib and cisplatin were identified as Mrp6 substrates. Survival probability after cisplatin administration was reduced in BDL mice. In conclusion, the present study demonstrated that BDL-induced cholestasis leads to the downregulation of the renal basolateral efflux transporter Mrp6, resulting in drug accumulation in renal cells and promoting drug-induced renal injury.

2023-08-22 | GSE212283 | GEO

Calnexin depletion by ER-stress during cholestasis inhibits the Na+-taurocholate Cotransporting Polypeptide (NTCP)

Project description:Impaired bile flow (cholestasis) leads to transcriptional downregulation of the bile acid importer Na+-taurocholate co-transporting protein (NTCP) and to ER-stress in the liver. Here, we show that ER-stress induction strongly reduces NTCP protein expression, plasma membrane abundance and NTCP-mediated bile acid uptake. This is not controlled via a single specific UPR-pathway but mainly depends on the interaction of NTCP with calnexin, an ER chaperone involved in folding of N-glycosylated proteins. In mice, expression of both Ntcp and calnexin was reduced by thapsigargin-induced ER-stress. Calnexin downregulation in HepG2 and U2OS cells results in a decreased NTCP expression and a reduced bile acid uptake. Calreticulin shows partial functional redundancy with calnexin as it also interacts with NTCP, and is downregulated upon ER-stress, but specifically in calnexin-depleted cells. In conclusion, ER stress-induced downregulation of calnexin provides an additional mechanism to dampen NTCP-mediated bile acid uptake during cholestasis.

2019-01-07 | PXD007948 | Pride

PGE2 promotes recovery from established Nephrotoxic Serum Nephritis in mice.

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Discrimination of etiologically different cholestasis by modeling proteomics datasets

Project description:Cholestasis is characterized by disrupted bile flow from the liver to the small intestine. Although etiologically different cholestasis display similar symptoms, diverse factors can contribute to the progression of the disease and determines the appropriate therapeutic option. Therefore, stratifying cholestatic patients is essential for the development of tailor-made treatment strategies. Here, we have analyzed the liver proteome from cholestatic patients of different etiology. 7,161 proteins were identified and quantified, of which 263 were differentially expressed between control and cholestasis groups. These differential proteins point to deregulated cellular processes that explain part of the molecular framework of cholestasis progression. However, the clustering of different cholestasis types was limited. Therefore, a machine learning pipeline was designed to identify a panel of 20 differential proteins that segregate different cholestasis groups with high accuracy and sensitivity. In summary, proteomics combined with machine learning algorithms provides valuable insights into the molecular mechanisms of cholestasis progression and a panel of proteins to discriminate across different types of cholestasis. This strategy may prove useful to develop precision medicine approaches for patient care.

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PGE2 promotes recovery from established Nephrotoxic Serum Nephritis in mice.

Project description:We induced acute nephritis by single injection of sheep nephrotoxic serum in mice and then treated the mice with prostaglandin E2. We used microarrays to examine the global gene expressions during recovery from nephrotoxic nephritis by prostaglandin E2. Acute nephristis was induced in female mice by single injection of sheep Nephortoxc Serum (NTS), followed by prostaglandin E2 administration daily starting from day 2 after NTS administration. Mice were sacrificed on day 7 and RNAs were isolated from kidney. The RNA samples were subjected to mouse gene 1.0 ST array analysis.

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Gene expression in B cells from mice with the autoimmune disease nephrotoxic nephritis

Project description:Studying the differences in glycosylation in B cells of normal mice and mice with an autoimmune disease (nephrotoxic nephritis). Differences in glycosylation in B cells of normal mice and mice with an autoimmune disease (nephrotoxic nephritis) were studied via gene expression analysis. RNA from mouse resting spleen B cells and B cells stimulated with antiCD40, CpG, and IL4 for 5 days, was isolated and prepared. One sample for each class was prepared. RNA was labeled and hybridized to the GLYCOv3 array. Resulting Gene expression patterns were analyzed.

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Project description:One single-cell RNA transcriptomic dataset was originated from one wild-type mouse, which was harvested at 3 months after nephrotoxic nephritis model.

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Gene expression in B cells from mice with the autoimmune disease nephrotoxic nephritis

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lncRNA downregulation

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