Chronic elevation of IL-1ß induces diuresis via a cyclooxygenase 2-mediated mechanism.

Chronic renal inflammation is an increasingly recognized phenomenon in multiple disease states, but the impact of specific cytokines on renal function is unclear. Previously, we found that 14-day interleukin-1ß (IL-1ß) infusion increased urine flow in mice. To determine the mechanism by which this occurs, the current study tested the possible involvement of three classical prodiuretic pathways. Chronic IL-1ß infusion significantly increased urine flow (6.5 ± 1 ml/day at day 14 vs. 2.3 ± 0.3 ml/day in vehicle group; P < 0.05) and expression of cyclooxygenase (COX)-2, all three nitric oxide synthase (NOS) isoforms, and endothelin (ET)-1 in the kidney (P < 0.05 in all cases). Urinary prostaglandin E metabolite (PGEM) excretion was also significantly increased at day 14 of IL-1ß infusion (1.21 ± 0.26 vs. 0.29 ± 0.06 ng/day in vehicle-infused mice; P = 0.001). The selective COX-2 inhibitor celecoxib markedly attenuated urinary PGEM excretion and abolished the diuretic response to chronic IL-1ß infusion. In contrast, deletion of NOS3, or inhibition of NOS1 with L-VNIO, did not blunt the diuretic effect of IL-1ß, nor did pharmacological blockade of endothelin ETA and ETB receptors with A-182086. Consistent with a primary effect on water transport, IL-1ß infusion markedly reduced inner medullary aquaporin-2 expression (P < 0.05) and did not alter urinary Na⁺ or K⁺ excretion. These data indicate a critical role for COX-2 in mediating the effects of chronic IL-1ß elevation on the kidney.

Endothelin receptor A-specific stimulation of glomerular inflammation and injury in a streptozotocin-induced rat model of diabetes.

AIMS/HYPOTHESIS: Activation of endothelin receptor-A (ET(A)) increases glomerular permeability to albumin (P(alb)) and elevates pro-inflammatory markers in hyperglycaemic rats. METHODS: Male Sprague-Dawley rats were given streptozotocin (n = 32) or saline (sham; n = 32). Half of the animals in each group received the ET(A)-selective antagonist, ABT-627 (atrasentan; orally), beginning immediately after hyperglycaemia was confirmed. Glomeruli were isolated by sieving techniques and P(alb) determined from the change in glomerular volume induced by oncotic gradients of albumin. Glomerular nephrin levels were assessed by immunofluorescence, whereas urinary nephrin was measured by immunoassay. RESULTS: At 3 and 6 weeks after streptozotocin injection, proteinuria was significantly increased compared with sham controls and significantly reduced by ABT-627 treatment. P(alb) was also increased at 3 and 6 weeks post-streptozotocin. ABT-627 had no effect on P(alb) or protein excretion in sham control rats. In glomeruli isolated from hyperglycaemic rats, incubation with BQ-123, a selective ET(A) antagonist, reduced P(alb), whereas BQ-788, a selective endothelin receptor-B antagonist had no effect (n = 6 rats per group, 5-8 glomeruli per rat). Glomerular and plasma content of soluble intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 were significantly increased 6 weeks after streptozotocin (ELISA). ABT-627 attenuated these increases. After 6 weeks of hyperglycaemia, glomerular nephrin content was decreased with a concurrent increase in urinary nephrin excretion. ABT-627 prevented glomerular nephrin loss in hyperglycaemic rats (n = 5-8 rats per group; eight groups). CONCLUSIONS/INTERPRETATION: These observations support the hypothesis that endothelin-1, via the ET(A) receptor, directly increases P(alb), possibly via nephrin loss, as well as early inflammation in the hyperglycaemic rat.

Acute pressure-natriuresis relationship following withdrawal of chronic noradrenaline infusion.

1. Pathological changes to the kidney, such as vascular remodelling, have been found in several models of hypertension and may contribute to the maintenance of hypertension or confer susceptibility to redeveloping hypertension after the original prohypertensive stimulus is withdrawn. 2. To investigate whether noradrenaline-induced hypertension induces persistent, functionally important changes to the kidney, the acute pressure-natriuresis relationship was characterized in anaesthetized rats under controlled neural and hormonal conditions following chronic (14 days) intravenous infusion of noradrenaline (48 microg/kg per h) or vehicle (0.04 mg/mL ascorbic acid and 0.156 mg/mL NaH2PO4 2 H2O in 10 IU/mL heparinized saline). 3. Conscious mean arterial pressure was significantly elevated by infusion of noradrenaline at 48 microg/kg per h (+10 +/- 2 mmHg at Day 14; P < 0.01 vs vehicle group). The acute relationships between arterial pressure and renal blood flow, glomerular filtration rate, Na+ excretion and urine flow were not significantly different between the noradrenaline- and vehicle-infused rats immediately after termination of noradrenaline infusion. 4. In summary, chronic intravenous noradrenaline infusion did not cause persistent changes in renal function, indicating that, in contrast with many models of hypertension, this model does not induce underlying prohypertensive changes to the kidney.