Increased thromboxane mediates the adverse renal effects of interleukin-2 in rats.
The capillary leak syndrome with decreased GFR and renal water and sodium retention after recombinant interleukin-2 (IL-2) administration may arise from endothelial activation via an increase in prostaglandin synthesis. This study was undertaken to better define the role of the prostaglandin system in the renal and metabolic effects of IL-2 administration in rats. The chronic administration of IL-2 (100,000 U/kg, thrice daily, ip) resulted in a significant increase in body weight, a decrease in GFR and in the urinary excretion of sodium and potassium, and an increase in the urinary excretion of thromboxane (TXB2). After combined IL-2 and low-dose indomethacin (1.7 mg/kg per day po), a significant decrease in body weight with normalization of GFR, of the urinary excretion of Na, and of urinary TXB2 was noted in animals receiving combined therapy as compared with those receiving IL-2 alone. In contrast, high-dose indomethacin administration (33.3 mg/kg po for the last 3 days of the study) was associated with a further decrease in GFR, enhancement of the sodium and potassium retention, and suppression of prostaglandin E2 excretion. The administration of the thromboxane receptor antagonist SQ 29548 in IL-2-treated rats led to a reversal of the fall in GFR induced by the lymphokine without significant changes in urinary sodium excretion. These results support the hypothesis that thromboxane is an important mediator of the renal and systemic effects of IL-2. These effects are reversed at least partly by low-dose indomethacin, which selectively suppresses thromboxane A2 (TXA2) synthesis, or by TXA2 receptor antagonism.
Rubinger
D
D
Nephrology and Hypertension Services, Hadassah University Hospital, Jerusalem, Israel.
Cohen
E
E
Haviv
Y
Y
Bernheim
J
J
Shiloni
E
E
Popovtzer
M M
MM
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003404:Creatinine / Q000378:metabolism; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007376:Interleukin-2 / Q000009:adverse effects*; D007668:Kidney / Q000187:drug effects*; D008297:Male; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011453:Prostaglandins / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D013929:Thromboxane B2 / Q000652:urine; D013931:Thromboxanes / Q000502:physiology*; D013997:Time Factors
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007376:Interleukin-2; D011448:Prostaglandin Antagonists; D011453:Prostaglandins; D017482:Receptors, Thromboxane; D013931:Thromboxanes; D013929:Thromboxane B2; C045749:SQ 29548; D003404:Creatinine; D007213:Indomethacin