Mineralocorticoid Receptor signaling emerges as a key mediator of Carfilzomib induced increase in blood pressure. Prophylactic potential of Eplerenone.
Introduction: Carfilzomib (Carfilzomib), is a first-line irreversible proteasome inhibitor indicated for relapsed/refractory multiple myeloma, presenting life-threatening cardiovascular adverse effects. Hypertension, is the commonest side effect of Carfilzomib, remaining of unknown pathogenicity. Purpose: Considering that management of Carfilzomib-related hypertension remains an unmet clinical need and the pivotal role of renal function in blood pressure regulation we sought to investigate the renal contribution in Carfilzomib-induced hypertension. Methods: Eighty C57Bl/6 mice were randomized to our previously established translational models: 1. Two-doses Protocol: i. Control (N/S 0.9%) ii. Carfilzomib (8 mg/kg) for two days and 2. Four-doses Protocol: i. Control (N/S 0.9%) ii. Carfilzomib (8mg/kg) for seven days intraperitoneally. Blood pressure (BP) was measured by tail cuffs and urine collection was performed. Kidneys underwent histological, proteomic, metabolomic and molecular signalling analyses. Subsequently, eplerenone, was orally co-administered with Carfilzomib to the mice daily (165mg/kg) in the four doses protocol. Results: Carfilzomib increased systolic BP and led to renal histological deficits only in the four doses protocol. Proteomic analysis presented that metabolism and small molecules transport pathways were dysregulated by Carfilzomib. Carfilzomib decreased diuresis and induced renal metabolic alterations, while it activated MR/SGK-1 signalling. Co-administration of Carfilzomib-eplerenone, maintained diuresis and SBP and prevented renal MR/SGK-1 activation. Conclusions: Activation of renal MR signalling by Carfilzomib, orchestrates water/salt retention and increases BP in vivo, which is related with acute kidney injury, an effect prevented by Eplerenone co-administration. Considering that Carfilzomib-related hypertension management remains an unmet clinical need, MR blockade emerges as a potent therapeutic approach against Carfilzomib-related hypertension. The dataset includes 12 raw files and 12 xlsx files. Raw files are uploaded with the name: "Proteomics_data_CFZ_project.zip". The files from the control samples are designated as: control_1_mm_PE.raw, control_2_mm_PE.raw, control_3_mm_PE.raw, control_4_mm_PE.raw, control_5_mm_PE.raw, control_6_mm_PE.raw, whereas the files from the Carfilzomib treated samples are designated as: CFZ1_MM_PE.raw, CFZ2_MM_PE.raw, CFZ3_MM_PE.raw, CFZ4_MM_PE.raw, CFZ5_MM_PE.raw, CFZ6_MM_PE.raw. All files were from samples of the four-doses Protocol: i. Control (N/S 0.9%) ii. Carfilzomib (8mg/kg) for seven days intraperitoneally. The 12 xlsx files are uploaded with the name: Protein_Identifications_CFZ_project.zip. These are the protein identification files and have the same name with the corresponding raw files.
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Raw files were analyzed with Proteome Discoverer 1.4 software package (Thermo Scientific) utilizing the Sequest search engine and the mouse (Mus musculus) database, downloaded from uniprot including 16935 reviewed entries. The search was performed using carbamidomethylation of cysteine as static and oxidation of methionine as dynamic modifications. Two missed cleavage sites, a precursor mass tolerance of 10 ppm and fragment mass tolerance of 0.05 Da were allowed. False discovery rate (FDR) validation was based on q value: target FDR: 0.01.