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Chronic Renal Medullary Infusion of Interleukin‐1 Receptor Antagonist Delays the Onset of Salt Sensitive Hypertension in Uninephrectomized Dahl SS Rats
Author(s) -
Dasinger John Henry,
AbaisBattad Justine M,
Lund Hayley,
Fehrenbach Daniel J,
Mattson David L
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1026.14
Subject(s) - medicine , endocrinology , renal medulla , blood pressure , medullary cavity , saline , mean arterial pressure , receptor antagonist , kidney , inflammasome , antagonist , receptor , heart rate
The Dahl SS rat is a well‐established model of salt‐sensitive hypertension and renal disease with the immune system contributing in the pathology of the disease. Recent work from our laboratory demonstrated that in response to a high salt challenge, in addition to increases in blood pressure and urinary albumin excretion, there is an upregulation of the Nod‐like receptor protein‐3 (NLRP3) inflammasome in the renal medulla. This upregulation of the NLRP3 inflammasome leads to a subsequent increase in interleukin 1 beta (IL‐1β) production. This proinflammatory cytokine has been shown to be elevated in hypertension in humans making it a potential therapeutic target for salt sensitive hypertension. Therefore, we tested the hypothesis that chronic renal medullary infusion of IL‐1 receptor antagonist (IL‐1RA) would attenuate the development of salt sensitive hypertension in the Dahl SS rat. Animals underwent a right uninephrectomy at 7 weeks of age to avoid compensatory changes in blood pressure from the contralateral kidney. After a week of recovery, the left femoral artery was cannulated to measure mean arterial pressure (MAP) while a chronically implanted medullary interstitial catheter was placed in the left kidney for continuous infusion IL‐1RA (600μg/day, n=5) or vehicle (0.9% NaCl saline, n=6). MAP was measured during a 4‐day period while animals were maintained on 0.4% NaCl chow then switched to a high salt (4.0% NaCl) challenge for a 10‐day. MAP did not differ between saline and IL‐1RA treated animals during the 0.4% diet period (127±3 mmHg vs 121±4 mmHg, P >0.05). However, following a 10‐day challenge of 4.0% NaCl diet, MAP was significantly reduced in the IL‐1RA treated rats compared to the saline‐treated rats (157±9 mmHg vs 176±5 mmHg, P< 0.05). Despite seeing a reduction in MAP, urinary albumin (118±18 vs 126±10 mg/day) and protein (284±28 vs 277±19 mg/day) excretion in IL‐1RA treated did not differ from saline‐treated rats. Furthermore, when medullary IL‐1β levels were measured by ELISA, there was no difference between the IL‐1RA treated rats compared to the saline‐treated rats (76±25 pg/mL vs. 83±11 pg/mL). In contrast to the effects of intarenal infusion, systemic administration of the same dose of IL‐1RA did not alter salt‐sensitive hypertension compared to vehicle‐treated control SS (132±8mmHg vs 141±mmHg, n=5–6/group), demonstrating that the effects observed with medullary interstitial infusion are due to intrarenal effects. These data indicate that blockade of the IL‐1 receptor in the renal medulla attenuates salt‐sensitive hypertension in the Dahl SS rat. Further studies are required to understand the mechanism by which renal medullary inhibition of IL‐1β results in reduction in blood pressure in response to a high salt diet. Support or Funding Information Supported by DK96859, HL116264, and 15SFRN2391002.