title: Interleukin-1 Receptor Activation Potentiates Salt Reabsorption in Angiotensin II-Induced Hypertension via the NKCC2 Co-transporter in the Nephron.
abstract: Hypertension is among the most prevalent and catastrophic chronic diseases worldwide. While the efficacy of renin angiotensin system (RAS) blockade in lowering blood pressure illustrates that the RAS is broadly activated in human hypertension, the frequent failure of RAS inhibition to prevent or reverse hypertensive organ damage highlights the need for novel therapies to combat RAS-dependent hypertension. We previously discovered elevated levels of the macrophage cytokine IL-1 in the kidney in a murine model of RAS-mediated hypertension. Here we report that IL-1 receptor (IL-1R1) deficiency or blockade limits blood pressure elevation in this model by mitigating sodium reabsorption via the NKCC2 co-transporter in the nephron. In this setting, IL-1R1 activation prevents intra-renal myeloid cells from maturing into Ly6C(+)Ly6G(-) macrophages that elaborate nitric oxide, a natriuretic hormone that suppresses NKCC2 activity. By revealing how the innate immune system regulates tubular sodium transport, these experiments should lead to new immunomodulatory anti-hypertensive therapies.
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, USA.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, USA.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Rudemiller
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, USA.
authors.forename: Mehul B
authors.initials: MB
authors.lastname: Patel
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, USA.
authors.forename: Norah S
authors.initials: NS
authors.lastname: Karlovich
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Alicia A
authors.initials: AA
authors.lastname: McDonough
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Griffiths
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Sparks
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, USA.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Jeffs
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, USA. Electronic address: steven.d.crowley@duke.edu.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Crowley
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009399:Nephrons / Q000378:metabolism* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D065608:Renal Reabsorption; D012084:Renin-Angiotensin System; D015398:Signal Transduction; D017673:Sodium Chloride, Dietary / Q000378:metabolism*; D064466:Solute Carrier Family 12, Member 1 / Q000378:metabolism*
chemical_list: D017472:Receptors, Interleukin-1; C578715:Slc12a1 protein, mouse; D017673:Sodium Chloride, Dietary; D064466:Solute Carrier Family 12, Member 1; D000804:Angiotensin II; D009569:Nitric Oxide