Chronic elevation of IL‐1β induces diuresis independently of endothelin: potential involvement of cyclo‐oxygenase and nitric oxide synthase pathways

Abstract

Chronic inflammation is an increasingly recognized phenomenon in cardiovascular disease and diabetes, but the impact of specific cytokines on renal function is unclear. Previously we found that 14-day interleukin-1β (IL-1β) infusion increased urine flow and renal endothelin-1 (ET-1) production in mice. To determine if the diuretic response to IL-1β is mediated by ET-1, mice received vehicle or IL-1β (10 ng/h) s.c. and were also treated or not with the combined ETA and ETB receptor antagonist A-182086 (30 mg/kg/d) for 14 days. IL-1β infusion significantly increased urine flow (6.5 ± 1 ml/d at day 14 vs 2.3 ± 0.3 ml/d in vehicle group; P<0.05) but this was not significantly attenuated by treatment with A-182086 (6.0 ± 1.2 ml/d). IL-1β infusion increased renal cortical mRNA levels (quantitative real time PCR) of nitric oxide synthase (NOS) 1, NOS 3 and cyclo-oxygenase (COX) 2 but not COX 1. The IL-1β induced upregulation of NOS 3 (2−ΔΔCT= 3.0 ± 0.3) was partially mediated by ET-1 as A-182086 significantly attenuated the IL-1β-induced increase in NOS 3 expression (2−ΔΔCT = 2.0 ± 0.2; P=0.01). IL-1β mediated increases in COX 2 and NOS 1 expression were not affected by A-182086. Treatment of vehicle-infused mice with A-182086 did not significantly affect urine flow or renal cortical expression of the aforementioned genes. These data show that the diuretic effects of chronic IL-1β infusion are not mediated by ET-1 but may instead involve upregulation of pro-diuretic COX and NOS pathways in the kidney.