Dataset Information

Renal Tubular Cells from Hibernating Squirrels are Protected against Cisplatin Induced Apoptosis.

ABSTRACT: Hibernating 13-lined ground squirrels are characterized by tolerance of severe hypothermia and hypoperfusion during torpor, followed by periodic warm reperfusion during IBA, conditions which are lethal to nonhibernating mammals. The aim of the present study was to determine whether protection from apoptosis was specific to torpor arousal cycles during hibernation or will also apply to cisplatin treatment on squirrel renal tubular cells (RTECs) that were procured during hibernation. Squirrel and mouse RTECs were treated with cisplatin, a potent inducer of RTEC apoptosis. Squirrel RTECs subjected to cisplatin had significantly less apoptosis, no cleaved caspase-3, and increased XIAP, pAkt, and pBAD versus mouse RTECs. To determine whether XIAP and Akt1 are necessary for RTEC protection against cisplatin induced apoptotic cell death, gene expression of Akt1 or XIAP was silenced in squirrel RTECs. Squirrel RTECs deficient in Akt1 and XIAP had increased apoptosis and cleaved caspase-3 when treated with cisplatin. Our results thus demonstrates that 13-lined ground squirrel RTECs possess intrinsic intracellular mechanisms by which they protect themselves from apoptotic cell death. Cisplatin induced acute kidney injury (AKI) may be avoided in cancer patients by employing mechanisms used by squirrel RTECs to protect against cisplatin induced tubular cell apoptosis.

SUBMITTER: Jain S

PROVIDER: S-EPMC7424393 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Renal Tubular Cells from Hibernating Squirrels are Protected against Cisplatin Induced Apoptosis.

Jain Swati S Jani Alkesh A

International journal of nephrology 20200804

Hibernating 13-lined ground squirrels are characterized by tolerance of severe hypothermia and hypoperfusion during torpor, followed by periodic warm reperfusion during IBA, conditions which are lethal to nonhibernating mammals. The aim of the present study was to determine whether protection from apoptosis was specific to torpor arousal cycles during hibernation or will also apply to cisplatin treatment on squirrel renal tubular cells (RTECs) that were procured during hibernation. Squirrel and ...[more]

PMID: 32832155

Similar Datasets

Project description:Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase that interacts with WD repeat domain 5 (WDR5) to regulate cell survival, proliferation, and senescence. The role of MLL1 in the pathogenesis of acute kidney injury (AKI) is unknown. In this study, we demonstrate that MLL1, WDR5, and trimethylated H3K4 (H3K4me3) were upregulated in renal tubular cells of cisplatin-induced AKI in mice, along with increased phosphorylation of p53 and decreased expression of E-cadherin. Administration of MM102, a selective MLL1/WDR5 complex inhibitor, improved renal function and attenuated tubular injury and apoptosis, while repressing MLL1, WDR5, and H3K4me3, dephosphorylating p53 and preserving E-cadherin. In cultured mouse renal proximal tubular cells (RPTCs) exposed to cisplatin, treatment with MM102 or transfection with siRNAs for either MLL1 or WDR5 also inhibited apoptosis and p53 phosphorylation while preserving E-cadherin expression; p53 inhibition with Pifithrin-α lowered cisplatin-induced apoptosis without affecting expression of MLL1, WDR5, and H3K4me3. Interestingly, silencing of E-cadherin offset MM102's cytoprotective effects, but had no effect on p53 phosphorylation. These findings suggest that MLL1/WDR5 activates p53, which, in turn, represses E-cadherin, leading to apoptosis during cisplatin-induced AKI. Further studies showed that MM102 effectively inhibited cisplatin-triggered DNA damage response (DDR), as indicated by dephosphorylation of ataxia telangiectasia mutated (ATM) and ATM and Rad-3 related (ATR) proteins, dephosphorylation of checkpoint kinase 1 and 2 (Chk1 and Chk2); depression of γ-H2AX; and restrained cell cycle arrest, as evidenced by decreased expression of p21 and phospho-histone H3 at serine 10 in vitro and in vivo. Overall, we identify MLL1 as a novel DDR regulator that drives cisplatin-induced RPTC apoptosis and AKI by modulating the MLL1/WDR5-/ATR/ATM-Chk-p53-E-cadherin axis. Targeting the MLL1/WDR5 complex may have a therapeutic potential for the treatment of AKI.

Dataset Information

Renal Tubular Cells from Hibernating Squirrels are Protected against Cisplatin Induced Apoptosis.

Publications

Renal Tubular Cells from Hibernating Squirrels are Protected against Cisplatin Induced Apoptosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets