Interleukin-1 Receptor Activation Potentiates Salt Reabsorption in Angiotensin II-Induced Hypertension via the NKCC2 Co-transporter in the Nephron

Abstract

Summary 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.

Elementary immunology: Na+ as a regulator of immunity

“…Harris and coworkers demonstrated that high salt diets increase the expression of cyclooxygenase-2 in renal mononuclear phagocytes and that this renal mononuclear phagocyte-driven prostaglandin production decreased the phosphorylation and activity of the renal Na + –Cl − cotransporter in the distal convoluted tubule in the renal cortex [29]. Using a mouse model of renin angiotensin system (RAS)-mediated hypertension, Crowley and coworkers discovered that interleukin (IL)-1 receptor signaling impairs the ability of intra-renal macrophages to facilitate tubular Na + excretion [30]. Excess aldosterone [31] as well as the treatment of uninephrectomized mice with deoxycorticosterone acetate and saline to drink [32] result in overproduction of IL-1β and thereby might impact on renal Na + handling.…”

High-Fiber Diet and Acetate Supplementation Change the Gut Microbiota and Prevent the Development of Hypertension and Heart Failure in Hypertensive Mice

“…37 Besides the higher levels of IL-1 usually detected in hypertensive subjects, 37 the activation of the IL-1 receptor leads to sodium retention in the kidney through a mechanism that involves macrophages and nitric oxide production. 38 Moreover, fiber and acetate led to the downregulation of the transcription factor Egr1, considered a master regulator because it controls the expression of a wide range of genes and pathways implicated in CVD processes. 29 Particularly relevant to the present study is the role of Egr1 in cardiac hypertrophy, renal fibrosis, and inflammation.…”

ISN Forefronts Symposium 2015: Maintaining Balance Under Pressure—Hypertension and the Proximal Tubule

“…35,36 A recent report from Crowley and colleagues suggests that inflammatory accumulation of IL-1 during hypertension activates loop of Henle Na + -K + -2Cl − cotransporter (NKCC2) which blunts the natriuresis and raises blood pressure; eliminating IL-1 limits the blood pressure elevation by reducing NKCC2 Na + reabsorption. 37 This study provides another example of how injury signals contribute to hypertension by blunting pressure natriuresis. In summary, regarding natriuretic signaling during hypertension, there is consensus that multiple signals have the potential to act all along the nephron, thus, the pressure natriuresis response is the sum of the prevailing natriuretic and anti-natriuretic influences.…”