Poster Session 1 - C5
1-2Luke S Dingwell, 1,3Eric A Shikatani, 3Rickvinder Besla, 4Andrew S Levy, 4Danny Dinh, 1Abdul Momen, 4Hangjun Zhang, 1Talat Afroze, 5Michelle B Chen, 4Nicholas Maksimowski, 5Craig A Simmons, 1Filio Billia, 6Jennifer L Gommerman, 3Rohan John, 4Scott Heximer, 4James Scholey, 4Steffen-Sebastian Bolz, 3,6Clinton Robbins, 1-4,7*Mansoor Husain
1 Ted Rogers Centre for Heart Research; Departments of 2 Institute of Medical Science, 3 Laboratory Medicine & Pathobiology, 4 Physiology, 5 Mechanical & Industrial Engineering, 6 Immunology, and 7 Medicine, University of Toronto, Toronto, ON, Canada
The proto-oncogene and nuclear transcription factor c-myb regulates differentiation of hematological and vascular smooth muscle cells; however, the role of c-Myb in integrated cardiovascular physiology is unknown. Mice homozygous for a hypomorphic c-myb allele (c-mybh/h) conferring reduced c-Myb activity have lower systolic and diastolic blood pressure, and reduced susceptibility to DOCA-salt experimental hypertension compared to wild-type (WT) mice. Although cardiac structure and function, and resistance artery function were normal, c-mybh/h mice have increased 24-h urine output, creatinine clearance, and sodium excretion vs. WT, and have reduced peripheral blood and kidney B220+ B-cells. Reconstitution of WT mice with c-mybh/h bone marrow transplant (BMT) (h/h>WT) decreased blood pressure of WT recipients to h/h levels, and increased 24-h urine output compared to control, WT>WT mice. Conversely, WT>h/h mice had blood pressure similar to WT mice. Chimeric BMT from i) c-mybh/h mice and ii) mice lacking B-cells (JHT) into WT mice (h/h:JHT>WT) lowered BP and increased 24-h urine output compared to control, WT:JHT>WT mice. B-cell deleted JHT mice were also found to manifest lower systolic and diastolic blood pressure and increased 24-h urine output compared to WT mice. qRT-PCR of kidney medulla found reduced vasopressin receptor 2 expression in c-mybh/h mice, implicating B-cells in the anti-diuretic hormone-vasopressin receptor 2 axis. Together, these data suggest that vasopressin receptor 2 deficiency in renal medulla results in abnormal salt- and water-handling and consequently, lower blood pressure in c-mybh/h mice. BMT and JHT experiments reveal the requirement of B-cells for blood pressure and renal homeostasis.