KCNK3 Mutation Causes Altered Immune Function in Pulmonary Arterial Hypertension Patients and Mouse Models

Abstract

Loss of function KCNK3 mutation is one of the gene variants driving hereditary pulmonary arterial hypertension (PAH). KCNK3 is expressed in several cell and tissue types on both membrane and endoplasmic reticulum and potentially plays a role in multiple pathological process associated with PAH. However, the role of various stressors driving the susceptibility of KCNK3 mutation to PAH is unknown. Hence, we exposed kcnk3fl/fl animals to hypoxia, metabolic diet and low dose lipopolysaccharide (LPS) and performed molecular characterization of their tissue. We also used tissue samples from KCNK3 patients (skin fibroblast derived inducible pluripotent stem cells, blood, lungs, peripheral blood mononuclear cells) and performed microarray, immunohistochemistry (IHC) and mass cytometry time of flight (CyTOF) experiments. Although a hypoxic insult did not alter vascular tone in kcnk3fl/fl mice, RNASeq study of these lungs implied that inflammatory and metabolic factors were altered, and the follow-up diet study demonstrated a dysregulation of bone marrow cells in kcnk3fl/fl mice. Finally, a low dose LPS study clearly showed that inflammation could be a possible second hit driving PAH in kcnk3fl/fl mice. Multiplex, IHC and CyTOF immunophenotyping studies on human samples confirmed the mouse data and strongly indicated that cell mediated, and innate immune responses may drive PAH susceptibility in these patients. In conclusion, loss of function KCNK3 mutation alters various physiological processes from vascular tone to metabolic diet through inflammation. Our data suggests that altered circulating immune cells may drive PAH susceptibility in patients with KCNK3 mutation.

Two-Pore-Domain Potassium (K2P-) Channels: Cardiac Expression Patterns and Disease-Specific Remodelling Processes

“…In the context of adrenal KCNK3 expression, a role of the K 2P 3.1 (TASK-1) channel in aldosterone secretion and blood pressure control is further discussed. Global Kcnk3 knockout mice display a phenotype of mild hyperaldosteronism [ 181 ] and single nucleotide polymorphisms in the KCNK3 gene were associated with plasma aldosterone levels [ 182 ]. Accordingly, elevated systolic blood pressure values were described in the Kcnk3 knockout mouse [ 25 ].…”

Identification of Prostate Cancer Risk Genetics Biomarkers Based on Intergraded Bioinformatics Analysis

“…The ROC curves further approved the accuracy of our risk model. It is reported that KCNK3 influenced physiological processes, ranging from vascular tone to metabolic diet through inflammation ( 48 ). Also, KCNK3 was correlated with prolonged survival after surgery in colorectal cancer ( 49 ).…”

Potassium Channels as Therapeutic Targets in Pulmonary Arterial Hypertension

“…Recent studies implicate altered immune response as an overlapping phenotype between PAH-patient-derived cells and a mouse KCNK3 knockout model, suggesting that alterations in immune cells may underlie susceptibility to PAH in patients with KCNK3 mutation [ 37 ]. Moreover, peripheral recirculating immune cells between healthy controls and KCNK3 hereditary PAH patients show significant differences, including a relative reduction in naïve CD8+ and CD4+ T cells and naïve B cells, and reciprocal increases in memory CD8+ and CD4+ T cells and double negative CD4−/CD8− T cells.…”

“…Moreover, peripheral recirculating immune cells between healthy controls and KCNK3 hereditary PAH patients show significant differences, including a relative reduction in naïve CD8+ and CD4+ T cells and naïve B cells, and reciprocal increases in memory CD8+ and CD4+ T cells and double negative CD4−/CD8− T cells. The authors of this study conclude that KCNK3 mutation may predispose to increased inflammation via multiple intrinsic pathways [ 37 ]. This area of research highlights additional potential points of intervention in KCNK3-mediated PAH beyond the KCNK3 channel complex itself.…”