Carfilzomib-Induced Hypertension Is Mediated By Ion Channel Dysregulation in the Kidneys; The Potent Role of AMP-Activated Kinase α

• Published in: Blood 2020-11, Vol.136 (Supplement 1), p.34-35
• Main Authors: Efentakis, Panagiotis, Lamprou, Sofia, Dimas, Polyzois, Dimitriou, Constantinos, Makridakis, Manousos, Tsoumani, Maria, Papanikolaou, Asimina, Kastritis, Efstathios, Vlachou, Antonia, Dimopoulos, Meletios A, Andreadou, Ioanna, Terpos, Evangelos
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2020-136916

Introduction: Carfilzomib (Cfz), an irreversible proteasome inhibitor (PI), is an approved agent against relapsed/refractory multiple myeloma (R/R MM). Cfz is associated with high incidence of cardiovascular adverse effects. Hypertension stands as the most frequent cardiovascular complication of Cfz. Even though thrombotic microangiopathy (TMA) is inculpated of Cfz’s hypertensive phenotype, its exact pathophysiology is still elusive. In our previous work, we showed that Cfz establishes cardiotoxicity in vivo in a Protein Phosphatase 2A (PP2A)-AMP-activated kinase α (AMPKα)-dependent manner (Efentakis P et al. Blood. 2019;133(7):710-723) but does not lead to a permanent vascular deficit, indicating that hypertension is not vascular derived [Efentakis P et al. IJMS 2020;21(15):E5185]. Taking under consideration that renal homeostasis plays an important role in blood pressure regulation we sought to (i) characterize the dose-dependent manifestation of Cfz-induced hypertension; (ii) investigate the molecular signaling of Cfz in the kidneys by proteomic and immunoblotting analyses and (iii) study the renal ion channels regulation. Methods: Forty C57Bl/6 mice (12-14 weeks of age) were randomly assigned to: (i) Acute Protocol: a. Control [Normal Saline (N/S) 0.9%] and b. Cfz (8mg/kg) for two days and (ii) Sub-acute Protocol: a) Control (N/S 0.9%,) and b) Cfz (8mg/kg) for seven days. Intraperitoneal administration of N/S 0.9% and Cfz was performed at two consecutive and on alternate days for the acute and sub-acute protocols respectively. At baseline and endpoint of the experiments, systolic (SBP) and diastolic blood pressure (DBP) were measured, and subsequently mice were sacrificed for the collection of blood and renal samples. Blood samples were collected in citrate buffer for hematological/coagulation profiling [prothrombin time (PT) and INR estimation] and for cleaved Von Willebrand Factor (cl. VWF) immunoblotting assessment as well as for blood testing of white blood cells (WBCs) and platelets. Renal samples underwent histological proteomic and molecular analyses. Results: SBP and DBP were found to be elevated in Cfz group only in the sub-acute protocol compared to control (SBP: 78.5±2.0 vs 68.2±0.7, p