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• W2207584752 abstract "•IL-1 receptor (IL-1R1) deficiency or blockade attenuates hypertension•IL-1R1 activation drives salt retention in hypertension by depleting nitric oxide•Intra-renal macrophages lacking IL-1R1 have enhanced nitric oxide generation•IL-1R1 mediates sodium retention in hypertension by suppressing NKCC2 activity 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. 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. Hypertension is among the most prevalent chronic diseases, impacting over a billion adults worldwide (Lawes et al., 2008Lawes C.M. Vander Hoorn S. Rodgers A. International Society of HypertensionGlobal burden of blood-pressure-related disease, 2001.Lancet. 2008; 371: 1513-1518Abstract Full Text Full Text PDF PubMed Scopus (1762) Google Scholar). The complications of uncontrolled hypertension, such as stroke, heart failure, and kidney disease, are associated with substantial morbidity and mortality. However, the precise etiology of blood pressure elevation remains unclear in most affected individuals. Moreover, large numbers of hypertensive patients have blood pressure elevation that is resistant to existing treatment options (Egan et al., 2011Egan B.M. Zhao Y. Axon R.N. Brzezinski W.A. Ferdinand K.C. Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008.Circulation. 2011; 124: 1046-1058Crossref PubMed Scopus (446) Google Scholar), highlighting the urgent need for novel therapies. A growing body of evidence has suggested that hypertension is an inflammatory disease. Reports of an inflammatory response during hypertension began to emerge several decades ago. Early biopsy studies revealed that immune cells figure prominently in the kidneys in patients with severe hypertension (Heptinstall, 1953Heptinstall R.H. Malignant hypertension; a study of fifty-one cases.J. Pathol. Bacteriol. 1953; 65: 423-439Crossref PubMed Scopus (30) Google Scholar). More recent epidemiological observations showed that low-grade inflammation marked by increased C-reactive protein (CRP), a surrogate marker for interleukin 1 (IL-1) activity, precedes the onset of essential hypertension, suggesting that inflammation plays a role in the genesis of hypertension (Libby et al., 2002Libby P. Ridker P.M. Maseri A. Inflammation and atherosclerosis.Circulation. 2002; 105: 1135-1143Crossref PubMed Scopus (5902) Google Scholar, Sesso et al., 2003Sesso H.D. Buring J.E. Rifai N. Blake G.J. Gaziano J.M. Ridker P.M. C-reactive protein and the risk of developing hypertension.JAMA. 2003; 290: 2945-2951Crossref PubMed Scopus (804) Google Scholar). Moreover, linkage studies have demonstrated that polymorphisms in the genes encoding members of the IL-1 signaling pathway have been associated with essential hypertension (Fragoso et al., 2010Fragoso J.M. Delgadillo H. Llorente L. Chuquiure E. Juárez-Cedillo T. Vallejo M. Lima G. Furuzawa-Carballeda J. Peña-Duque M.A. Martínez-Ríos M.A. Vargas-Alarcón G. Interleukin 1 receptor antagonist polymorphisms are associated with the risk of developing acute coronary syndrome in Mexicans.Immunol. Lett. 2010; 133: 106-111Crossref PubMed Scopus (23) Google Scholar, Khawaja et al., 2008Khawaja M.R. Taj F. Saleheen D. Ahmad U. Chohan M.O. Jafar T. Frossard P.M. Association study of two interleukin-1 gene loci with essential hypertension in a Pakistani Pathan population.J. Hum. Hypertens. 2008; 22: 60-62Crossref PubMed Scopus (3) Google Scholar). IL-1 is a pro-inflammatory cytokine that plays a central role in both acute and chronic inflammation, acting as a primary inducer of the innate immune response. Both isoforms of IL-1, IL-1α and IL-1β, bind and signal via the type 1 IL-1 receptor (IL-1R1). We previously reported that expressions of both IL-1 isoforms are increased in the kidney during hypertension induced by activation of the renin angiotensin system (RAS) and correlate with the degree of blood pressure regulation (Crowley et al., 2010bCrowley S.D. Song Y.S. Sprung G. Griffiths R. Sparks M. Yan M. Burchette J.L. Howell D.N. Lin E.E. Okeiyi B. et al.A role for angiotensin II type 1 receptors on bone marrow-derived cells in the pathogenesis of angiotensin II-dependent hypertension.Hypertension. 2010; 55: 99-108Crossref PubMed Scopus (73) Google Scholar). However, studies that directly address the role of IL-1R1 signaling in the pathogenesis of hypertension are lacking. The present studies therefore test the hypothesis that activation of the IL-1R1 contributes to RAS-dependent hypertension. Herein, we elucidate a novel mechanism through which IL-1R1 stimulation potentiates blood pressure elevation by suppressing nitric oxide (NO)-dependent sodium excretion in the kidney. These experiments further identify IL-1R1 blockade as a potential strategy for treating hypertension. As IL-1α and β are both upregulated in the kidney during RAS-dependent hypertension (Crowley et al., 2010bCrowley S.D. Song Y.S. Sprung G. Griffiths R. Sparks M. Yan M. Burchette J.L. Howell D.N. Lin E.E. Okeiyi B. et al.A role for angiotensin II type 1 receptors on bone marrow-derived cells in the pathogenesis of angiotensin II-dependent hypertension.Hypertension. 2010; 55: 99-108Crossref PubMed Scopus (73) Google Scholar) and bind to the type 1 IL-1 receptor (IL-1R1), we first examined the contribution of the IL-1 signaling pathway to hypertension by subjecting wild-type (WT) and IL-1R1-deficient (knockout [KO]) mice to our angiotensin (Ang) II-dependent hypertension model. At baseline, WT and IL-1R1 KO mice had similar mean arterial blood pressures as measured by radiotelemetry (126 ± 1 versus 132 ± 3 mmHg; p = NS; Figure 1A). However, during chronic Ang II infusion, the IL-1R1 KO animals were partially protected from hypertension compared to the WT controls (165 ± 6 versus 180 ± 3 mmHg; p = 0.048; Figure 1A). Consistent with their lower blood pressures, the Ang II-infused IL1R1 KOs had less cardiac hypertrophy following 4 weeks of hypertension (7.5 ± 0.2 versus 9.2 ± 0.2 mg heart weight/g body weight, p < 0.0001; Figure 1C). We then examined whether pharmacological blockade of IL-1R1 affords similar protection from hypertension by administering an IL-1R1 antagonist (anakinra) or vehicle to WT mice for 3 days prior to and during chronic Ang II infusion. As seen with IL-1R1 deficiency, anakinra treatment in WT mice did not influence baseline blood pressures compared to vehicle-treated controls (130 ± 3 versus 130 ± 1 mmHg; p = NS; Figure 1B). However, IL-1R1 blockade with anakinra significantly attenuated the level of blood pressure elevation during chronic Ang II infusion (154 ± 4 versus 167 ± 3 mmHg; p = 0.029; Figure 1B), leading to less cardiac hypertrophy after 4 weeks of hypertension (6.4 ± 0.3versus 7.1 ± 0.2 mg heart weight/g body weight, p = 0.05; Figure 1D). These data suggest that IL-1 receptor stimulation potentiates Ang II-mediated blood pressure elevation. To determine whether the pro-hypertensive effects of IL-1 receptor activation were related to renal sodium retention, we placed WT and IL-1R1 KO mice into metabolic cages beginning 1 week prior to the initiation of chronic Ang II infusion and quantitated daily sodium ingestion and urinary sodium excretion to compute net sodium balances. Food ingestion remained similar in the two groups throughout the study (Figure S1A). Prior to Ang II, the two groups had similar net sodium balances (Figure 2A) and levels of urinary sodium excretion (Figure 2B). However, concurrent with the separation in blood pressures during the second week of Ang II infusion, the WT animals excreted less sodium than their IL-1R1 KO counterparts (Figure 2B). Accordingly, over days 10–15 of Ang II, the WT mice sustained a positive sodium balance, whereas the IL-1R1 KO mice switched to a negative sodium balance (208.84 ± 44.84 versus −100.66 ± 100.74 μmol/6 days, p = 0.013). Thus, IL-1 receptor deficiency limits Ang II-induced sodium reabsorption, mitigating the hypertensive response in our model. The actions of the IL-1 receptor to potentiate sodium retention appear to require RAS stimulation, as salt-loading at baseline had a similar impact to raise blood pressures in the WT and IL-1R1 KO cohorts (Figure 2C). To further examine the mechanism responsible for the attenuated hypertension and enhanced natriuresis in the IL-1R1 KO cohort, we measured the activity of two key renal sodium transporters, NKCC2 and NCC, either at baseline or following 10 days of chronic Ang II infusion when the difference in sodium excretion between the groups was most evident. To evaluate sodium transporter activity at these time points, we quantitated diuretic-induced sodium excretion during the 3 hr after an intraperitoneal saline infusion. At baseline prior to Ang II, there were no differences in sodium excretion between WT and IL1R1 KO mice either in response to saline control (90.3 ± 16.9 versus 62.3 ± 12.9 mmol Na+/mmol Cr, p = NS) or furosemide (408.9 ± 89.2 versus 499.4 ± 123.0 mmol Na+/mmol Cr, p = NS; Figure 2D). By contrast, at day 10 of Ang II infusion, in response to IP saline injection alone, the IL-1R1 KO mice had exaggerated urine sodium to creatinine ratios, consistent with their enhanced natriuresis during hypertension in our original balance study (236.9 ± 38.2 versus 119.5 ± 8.8 mmol/mmol Cr; p = 0.016; Figure 2E). Blockade of NKCC2 with furosemide increased sodium excretion in both groups but abrogated the difference between the WT and IL-1R1 KOs (453.4 ± 55.5 versus 480.5 ± 103.1 mmol/mmol Cr; p = 0.83; Figure 2E), suggesting that impaired NKCC2 activity in the Ang II-infused IL-1R1 KO mice accounts for their preserved capacity to excrete sodium during chronic Ang II infusion. Given the potential confounder of tubular creatinine secretion, we repeated the analysis without normalizing sodium excretion for creatinine and noted the same pattern (Figure S1B). By contrast, blockade of the NCC sodium transporter with hydrochlorthiazide did not attenuate the differences in sodium excretion between the Ang II-infused WT and IL-1R1 KOs (data not shown). At day 10 of Ang II, western blot analysis revealed similar levels of total and phosphorylated NKCC expression in the renal cortex and medulla of the two groups (Figure 2F; Figure S1D), suggesting that IL-1 receptor activation modulates the function of NKCC without altering its translation or phosphorylation. To determine whether chronic in vivo NKCC2 blockade could prevent the separation in blood pressures between the Ang II-infused WT and IL-1R1 KO mice, we administered furosemide in the drinking water for a week beginning on day 5 of Ang II before the WT and IL-1R1 blood pressures diverged. Over the first 5 days of Ang II prior to furosemide treatment, blood pressures in the groups were similar. Oral furosemide significantly reduced blood pressures in both groups and prevented the separation in WT and IL-1R1 KO blood pressures (Figure S1C). Thus, IL-1R1 stimulation promotes Ang II-induced sodium reabsorption via the NKCC2 co-transporter. IL-1 receptor stimulation could also regulate blood pressure and sodium excretion in our model by influencing vascular responses to Ang II (Vallejo et al., 2014Vallejo S. Palacios E. Romacho T. Villalobos L. Peiró C. Sánchez-Ferrer C.F. The interleukin-1 receptor antagonist anakinra improves endothelial dysfunction in streptozotocin-induced diabetic rats.Cardiovasc. Diabetol. 2014; 13: 158Crossref PubMed Scopus (77) Google Scholar). We therefore quantitated blood pressure elevation following an acute IV injection of Ang II into anesthetized animals (Figure S2A). By this measure, acute vascular responses of the IL-1R1 KO mice were intact. Moreover, renal vasoconstrictor responses as measured by reductions in renal blood flow following acute Ang II infusion were similar in anesthetized WT and IL-1R1 KO animals (Figure S2B). As an estimate of glomerular filtration rate (GFR), serum creatinines were comparable in the two groups at day 9 of chronic Ang II infusion (Figure S2C). These data would indicate that IL-1 receptor stimulation does not enhance Ang II-induced sodium retention by limiting delivery of sodium to the nephron. Nitric oxide (NO) can facilitate renal sodium excretion by suppressing NKCC2 activity (Ortiz et al., 2001Ortiz P.A. Hong N.J. Garvin J.L. NO decreases thick ascending limb chloride absorption by reducing Na(+)-K(+)-2Cl(-) cotransporter activity.Am. J. Physiol. Renal Physiol. 2001; 281: F819-F825Crossref PubMed Scopus (152) Google Scholar). We therefore examined 24 hr urinary excretion of nitric oxide metabolites as a marker of local NO production following 7 days of Ang II when the WT and IL-1R1 KO blood pressures diverged. As shown in Figure 3A, there was a 2.5-fold higher level of NO metabolites in the urines from the IL-1R1 KO cohort (152.5 ± 45.73 versus 60.32 ± 14.77 nmol/24 hr; p = 0.05). Inversely, reactive oxygen species can limit NO bioavailability, and the Ang II-infused IL-1R1 group had significantly less urinary excretion of 8-isoprostane that marks renal oxidative stress (p = 0.04; Figure 3B). These studies show that IL-1R1 deficiency preserves NO bioavailability during Ang II-dependent hypertension. To explore whether the enhanced NO bioavailability in the IL-1R1 KOs was responsible for their lower blood pressures in our hypertension model, we disrupted NO generation in both groups by administering L-NAME in the drinking water starting at day 7 of Ang II infusion. Similar to our initial hypertension experiment, IL1R1 KO mice had lower blood pressures than WT controls by day 7 of Ang II prior to L-NAME (165.4 ± 3.2 versus 179.3 ± 3.2 mm Hg; p = 0.006; Figure 3C). However, after L-NAME treatment, blood pressures in the groups converged (185.1 ± 12.7 versus 185.3 ± 4.8 mmHg; p = NS; Figure 3C). Thus, deprivation of NO bioavailability by L-NAME abrogated the protection from RAS-mediated blood pressure elevation in the IL1R1 KO mice, indicating that Ang II induces renal sodium retention and hypertension in part via IL-1R1-dependent suppression of NO generation. Next, we sought to determine which of the NO synthases contributed to the exaggerated NO production in the Ang II-infused IL1R1 KO mice. Whole kidney mRNA expression of NOS3 (eNOS) was similar in the the groups (Figure 3D). By contrast, NOS2 (iNOS) expression was markedly upregulated in the IL-1R1 KO kidneys compared to WT controls (1.73 ± 0.29 versus 1 ± 0.16 arbitrary units [a.u.]; p = 0.045; Figure 3E). Thus, NOS2 rather than NOS3 appears to drive the exaggerated production of NO in the IL-1R1-deficient kidney during Ang II-dependent hypertension. As NOS2 catalyzes the generation of NO in macrophages infiltrating target organs and IL-1R1 can modulate macrophage function, we quantitated the number of F4/80+ macrophages infiltrating the kidney following chronic Ang II infusion. This analysis revealed 32% more intra-renal macrophages in the IL-1R1 KO kidney compared to WT controls (17.9 ± 0.8 versus 13.6 ± 1.7 per high power field; p = 0.033; Figures 4A–4C). However, CD11b+ macrophages isolated from the kidneys of IL-1R1 KO animals at day 7 of Ang II expressed lower mRNA levels for the genes encoding pro-inflammatory cytokines (Figure 4D) including IL-1β (0.68 ± 0.06 versus 1.00 ± 0.05 a.u.; p = 0.004) and tumor necrosis factor-α (TNF) (0.65 ± 0.07 versus 1.00 ± 0.17 a.u.; p = 0.05). We therefore posited that the infiltrating macrophages in the IL-1R1 KO cohort were suppressing the hypertensive response through the generation of NO. To test this possibility, we used a fluorescent cell sorting strategy to isolate CD45+ infiltrating mononuclear cells from the WT or IL-1R1 kidney at day 7 of Ang II and labeled these cells for CD11b and Ly6C to mark activated infiltrating macrophages. During the isolation procedure, we exposed these macrophages to diaminofluorescein (DAF-FM), which fluoresces green when conjugated to NO. Macrophages from the IL1R1 KO kidneys had nearly 2-fold greater DAF staining for NO than WT controls (4.1% ± 0.6% versus 2.1% ± 0.5% of total infiltrating macrophages; p = 0.039; Figures 4E–4G), suggesting that IL-1R1 stimulation limits the accumulation of NO-producing macrophages in the hypertensive kidney. Finally, as macrophages expressing the marker Ly6C but not the granulocyte marker Ly6G are capable of elaborating NO (Youn et al., 2008Youn J.I. Nagaraj S. Collazo M. Gabrilovich D.I. Subsets of myeloid-derived suppressor cells in tumor-bearing mice.J. Immunol. 2008; 181: 5791-5802Crossref PubMed Scopus (1300) Google Scholar), we further stratified the CD45+ cells isolated from the hypertensive kidney based on their expression of these two markers to determine whether activation of the IL-1R1 influences the maturation of renal myeloid-derived cells. Among the IL-1R1 KO macrophages, there were 50% more Ly6C+ Ly6G− cells (17.4% ± 1.8% versus 11.1% ± 1.0%; p = 0.002; Figures 4H–4J) and 60% fewer immature myeloid cells marked by double positivity for both Ly6C and Ly6G (6.4% ± 1.3% versus 15.4% ± 3.0%; p = 0.015; Figures 4H–4J). Moreover, upon re-stimulation of the renal infiltrating macrophages with LPS (Figure S3), the induction of NOS2 expression as measured by flow cytometry in the Ly6C+ Ly6G− cells was 2-fold greater in the IL-1R1 KOs than in WT controls (9.6 ± 2.1 versus 4.1 ± 9.9 a.u.; p < 0.03). These data suggest that during RAS-dependent hypertension, IL-1R1 stimulation potentiates blood pressure elevation by suppressing the differentiation in the kidney of Ly6C+ Ly6G+ immature myeloid cells toward Ly6C+ Ly6G− myeloid cells that can elaborate NO and thereby constrain NKCC2-mediated sodium reabsorption. The pathogenesis of hypertension involves dysregulation of a complex circuit integrating inputs from the nervous system, the heart and vasculature, the kidney, and the immune system. Within the adaptive immune system, activated T lymphocytes can impart blood pressure elevation or reduction depending on the cytokines they elaborate (Barhoumi et al., 2011Barhoumi T. Kasal D.A. Li M.W. Shbat L. Laurant P. Neves M.F. Paradis P. Schiffrin E.L. T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury.Hypertension. 2011; 57: 469-476Crossref PubMed Scopus (317) Google Scholar, Guzik et al., 2007Guzik T.J. Hoch N.E. Brown K.A. McCann L.A. Rahman A. Dikalov S. Goronzy J. Weyand C. Harrison D.G. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction.J. Exp. Med. 2007; 204: 2449-2460Crossref PubMed Scopus (1295) Google Scholar, Madhur et al., 2010Madhur M.S. Lob H.E. McCann L.A. Iwakura Y. Blinder Y. Guzik T.J. Harrison D.G. Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction.Hypertension. 2010; 55: 500-507Crossref PubMed Scopus (543) Google Scholar). Within the innate immune system, monocytes can increase blood pressure through effects on vascular remodeling (Wenzel et al., 2011Wenzel P. Knorr M. Kossmann S. Stratmann J. Hausding M. Schuhmacher S. Karbach S.H. Schwenk M. Yogev N. Schulz E. et al.Lysozyme M-positive monocytes mediate angiotensin II-induced arterial hypertension and vascular dysfunction.Circulation. 2011; 124: 1370-1381Crossref PubMed Scopus (353) Google Scholar), dendritic cells can promote hypertension by presenting antigens to T cells (Kirabo et al., 2014Kirabo A. Fontana V. de Faria A.P. Loperena R. Galindo C.L. Wu J. Bikineyeva A.T. Dikalov S. Xiao L. Chen W. et al.DC isoketal-modified proteins activate T cells and promote hypertension.J. Clin. Invest. 2014; 124: 4642-4656Crossref PubMed Scopus (308) Google Scholar), and tissue macrophages can ameliorate salt-sensitive hypertension by facilitating the removal of excess sodium stores from the skin (Machnik et al., 2009Machnik A. Neuhofer W. Jantsch J. Dahlmann A. Tammela T. Machura K. Park J.-K. Beck F.-X. Müller D.N. Derer W. et al.Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism.Nat. Med. 2009; 15: 545-552Crossref PubMed Scopus (699) Google Scholar, Wiig et al., 2013Wiig H. Schröder A. Neuhofer W. Jantsch J. Kopp C. Karlsen T.V. Boschmann M. Goss J. Bry M. Rakova N. et al.Immune cells control skin lymphatic electrolyte homeostasis and blood pressure.J. Clin. Invest. 2013; 123: 2803-2815Crossref PubMed Scopus (287) Google Scholar). In this context, the current experiments reveal an additional pathogenic immune mechanism in hypertension wherein IL-1 receptor stimulation blocks the accumulation in the kidney of NO-producing myeloid cells that can mitigate NKCC2-mediated sodium retention. Several lines of evidence prompted us to focus on a possible role for IL-1 receptor activation in hypertension. Elevated serum levels of IL-1β have been documented in patients with essential hypertension (Dalekos et al., 1996Dalekos G.N. Elisaf M.S. Papagalanis N. Tzallas C. Siamopoulos K.C. Elevated interleukin-1 beta in the circulation of patients with essential hypertension before any drug therapy: a pilot study.Eur. J. Clin. Invest. 1996; 26: 936-939Crossref PubMed Scopus (35) Google Scholar) and in stroke-prone spontaneously hypertensive rats (Chiba et al., 2012Chiba T. Itoh T. Tabuchi M. Nakazawa T. Satou T. Interleukin-1β accelerates the onset of stroke in stroke-prone spontaneously hypertensive rats.Mediators Inflamm. 2012; 2012: 701976Crossref PubMed Scopus (23) Google Scholar). Also in rats, infusion of IL-1b into the intracerebral ventricles, the paraventricular nucleus, or the systemic venous circulation yielded an acute pressor response (Lu et al., 2009Lu Y. Chen J. Yin X. Zhao H. Angiotensin II receptor 1 involved in the central pressor response induced by interleukin-1 beta in the paraventricular nucleus.Neurol. Res. 2009; 31: 420-424Crossref PubMed Scopus (19) Google Scholar, Takahashi et al., 1992Takahashi H. Nishimura M. Sakamoto M. Ikegaki I. Nakanishi T. Yoshimura M. Effects of interleukin-1 beta on blood pressure, sympathetic nerve activity, and pituitary endocrine functions in anesthetized rats.Am. J. Hypertens. 1992; 5: 224-229Crossref PubMed Scopus (78) Google Scholar, Yamamoto et al., 1994Yamamoto T. Kimura T. Ota K. Shoji M. Inoue M. Ohta M. Sato K. Funyu T. Abe K. Effects of interleukin-1 beta on blood pressure, thermoregulation, and the release of vasopressin, ACTH and atrial natriuretic hormone.Tohoku J. Exp. Med. 1994; 173: 231-245Crossref PubMed Scopus (13) Google Scholar). Finally, we previously detected elevated expression levels of IL-1α and β in the kidney during hypertension driven by activation of the renin angiotensin system (RAS) (Crowley et al., 2010bCrowley S.D. Song Y.S. Sprung G. Griffiths R. Sparks M. Yan M. Burchette J.L. Howell D.N. Lin E.E. Okeiyi B. et al.A role for angiotensin II type 1 receptors on bone marrow-derived cells in the pathogenesis of angiotensin II-dependent hypertension.Hypertension. 2010; 55: 99-108Crossref PubMed Scopus (73) Google Scholar). To capture signaling of both IL-1 isoforms, we have tested the effects of IL-1 receptor (IL-1R1) deficiency or blockade on the hypertensive response to chronic angiotensin (Ang) II infusion, the same model in which we previously detected IL-1 upregulation. We also favor this model as large percentages of patients treated with RAS blockade respond with some degree of blood pressure reduction, suggesting that the RAS is inappropriately activated in human hypertension (Matchar et al., 2008Matchar D.B. McCrory D.C. Orlando L.A. Patel M.R. Patel U.D. Patwardhan M.B. Powers B. Samsa G.P. Gray R.N. Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension.Ann. Intern. Med. 2008; 148: 16-29Crossref PubMed Scopus (284) Google Scholar). Using both genetic and pharmacological approaches, we find that IL-1R1 signaling makes a striking and persistent contribution to Ang II-mediated blood pressure elevation. RAS activation causes chronic hypertension by driving sodium retention in the kidney (Crowley et al., 2006Crowley S.D. Gurley S.B. Herrera M.J. Ruiz P. Griffiths R. Kumar A.P. Kim H.S. Smithies O. Le T.H. Coffman T.M. Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney.Proc. Natl. Acad. Sci. USA. 2006; 103: 17985-17990Crossref PubMed Scopus (523) Google Scholar, Gonzalez-Villalobos et al., 2013Gonzalez-Villalobos R.A. Janjoulia T. Fletcher N.K. Giani J.F. Nguyen M.T. Riquier-Brison A.D. Seth D.M. Fuchs S. Eladari D. Picard N. et al.The absence of intrarenal ACE protects against hypertension.J. Clin. Invest. 2013; 123: 2011-2023Crossref PubMed Scopus (157) Google Scholar). Moreover, we noted a gradual separation in WT and IL-1R1 KO blood pressures after a week of Ang II when prominent natriuresis can occur (Crowley et al., 2010aCrowley S.D. Song Y.S. Lin E.E. Griffiths R. Kim H.S. Ruiz P. Lymphocyte responses exacerbate angiotensin II-dependent hypertension.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010; 298: R1089-R1097Crossref PubMed Scopus (181) Google Scholar), leading us to explore whether IL-1R1 stimulation influences renal sodium handling during RAS activation. We find that IL-1R1 signaling exaggerates Ang II-induced sodium retention, preventing the natriuresis that would otherwise occur in response to substantial elevations in blood pressure. As the timings of the separations in blood pressure and sodium balances do not match precisely, we speculate that the metabolic cage conditions used for the balance studies may have attenuated eating and drinking behaviors and that mobilization of non-osmotic dermal sodium stores contributed to the net sodium balances in both groups (Machnik et al., 2009Machnik A. Neuhofer W. Jantsch J. Dahlmann A. Tammela T. Machura K. Park J.-K. Beck F.-X. Müller D.N. Derer W. et al.Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism.Nat. Med. 2009; 15: 545-552Crossref PubMed Scopus (699) Google Scholar). Nevertheless, the higher sodium excretion coupled with lower blood pressures in the Ang II-infused IL-1R1 KOs suggests that their natriuresis caused rather than compensated for their blunted hypertensive response compared to WT controls. The discovery that IL-1R1 activation potentiates salt reabsorption in our model is unexpected as acute IL-1 administration can inhibit sodium reabsorption in the collecting duct (Kohan et al., 1989Kohan D.E. Merli C.A. Simon E.E. Micropuncture localization of the natriuretic effect of interleukin 1.Am. J. Physiol. 1989; 256: F810-F813PubMed Google Scholar, Sakairi et al., 1994Sakairi Y. Ando Y. Tabei K. Kusano E. Asano Y. Interleukin-1 inhibits sodium and water transport in rabbit cortical collecting duct.Am. J. Physiol. 1994; 266: F674-F680PubMed Google Scholar). We speculate that the effects of IL-1 on renal sodium handling may be bi-phasic in which mild IL-1 elevations occurring in hypertension favor salt retention, whereas fulminant IL-1 elevations during sepsis trigger natriuresis with a risk of circulatory collapse (Caverzasio et al., 1987Caverzasio J. Rizzoli R. Dayer J.M. Bonjour J.P. Interleukin-1 decreases renal sodium reabsorption: possible mechanism of endotoxin-induced natriuresis.Am. J. Physiol. 1987; 252: F943-F946PubMed Google Scholar). Such a phenomenon has been described with another pro-inflammatory cytokine, TNF (Ramseyer and Garvin, 2013Ramseyer V.D. Garvin J.L. Tumor necrosis factor-α: regulation of renal function and blood pressure.Am. J. Physiol. Renal Physiol. 2013; 304: F1231-F1242Crossref PubMed Scopus (103) Google Scholar). The apparent discrepancies in IL-1 actions could also be related to the source and distribution of IL-1 within the kidney as macrophages infiltrating the interstitium are likely a promin" @default.
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• W2207584752 date "2016-02-01" @default.
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• W2207584752 title "Interleukin-1 Receptor Activation Potentiates Salt Reabsorption in Angiotensin II-Induced Hypertension via the NKCC2 Co-transporter in the Nephron" @default.
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