Activation of peritoneal macrophages during the evolution of type 1 diabetes (insulitis) in streptozotocin-treated mice

The effects of lipopolysaccharide (LPS) and desArg9Bradykinin (DBK) on the release of nitric oxide (NO) from macrophages of mice 8, 12 and 18 days after having been treated with low doses of streptozotocin (STZ; 5 × 45 mg/kg) were studied. The results showed that LPS stimulated the release of NO from macrophages of untreated animals by 50% whereas the bradykinin B1 agonist desArg9Bradykinin (DBK) increased the level of NO by 20%. This increased NO production was totally abolished by incubating the cells with R-954, a selective bradykinin B1 antagonist. The release of NO from macrophages of STZ-treated mice incubated in the presence of LPS was more marked and reached approximately 220, 300 and 270% respectively from cells collected 8, 12 and 18 days after the STZ treatment. These significant increases were completely blocked by R-954 and were even below control values. Similarly the results showed that DBK stimulated by 50–75% the release of NO from macrophages of STZ-treated mice. The most marked stimulation was noted when the cells were collected 18 days after the treatment of the animals with STZ. Again in this set of experiments the B1 antagonist completely blocked the release of NO which went even below control values. The results clearly suggest the upregulation of bradykinin B1 receptors in mouse macrophages in the early phase of STZ-induced diabetes, an event that could even precede the onset of the diabetic hyperglycemia.

Research highlights▶ Macrophages from diabetic mice (STZ treatment) release NO following stimulation with lipopolysaccharide and desArg9Bradykinin. ▶ A selective bradykinin B1 receptor antagonist, R-954, blocks the release of NO which suggests the involvement of bradykinin B1 receptors in this process. ▶ The release of NO from macrophages of STZ-treated mice precedes the development of hyperglycemia.