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Published on: June 7, 2014
Renal effects of supernatant from rat peritoneal macrophages activated by microcystin-LR: role protein mediators
A C L Nobre1, A M C Martins, A Havt
1Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Rua Cel Nunes de Melo, 1127, Fortaleza, CE 60430-270, Brazil.
Abstract:
We have demonstrated previously that microcystin-LR promoted some renal alterations using the isolated perfused rat kidney preparation. However, these effects were not proved to be direct or indirect. The aim of the current work is to examine the renal effects promoted by supernatants from rat macrophages stimulated with microcystin-LR and the role of inflammatory mediators. Peritoneal macrophages were collected previously and were incubated for 1h in fresh medium (control) and in medium containing microcystin-LR. Dexamethasone, quinacrine, thalidomide and cycloheximide were administered 30 min before microcystin-LR. Supernatants of macrophages stimulated with or without pharmacological inhibitors were added on the perfused rat kidney model. The infusion of macrophages supernatants stimulated by microcystin-LR caused significant increases in renal vascular resistance (C: 4.93+/-0.33 vs T: 5.15+/-0.21), glomerular filtration rate (C: 0.559+/-0.008 vs T: 0.978+/-0.15) and urinary flow (C: 0.16+/-0.01 vs T: 0.23+/-0.03). Cycloheximide, quinacrine and dexamethasone blocked these effects and thalidomide blocked renal vascular resistance. Macrophages stimulated by microcystin-LR release mediators capable of promoting nephotoxicity in isolated perfused rat kidney. Phospholipase A(2), TNF-alpha and other protein mediators appear to be involved on its renal toxic mechanism.
Insights
Microcystin-LR triggers kidney damage indirectly through macrophage-released inflammatory mediators. Inhibiting phospholipase A(2) and protein synthesis blocked these harmful nephrotoxic effects.
Area of Science:
- Toxicology
- Immunology
- Nephrology
Background:
- Microcystin-LR is known to cause renal alterations.
- Previous studies could not determine if these effects were direct or indirect.
Purpose of the Study:
- To investigate the renal effects of supernatants from microcystin-LR-stimulated rat macrophages.
- To elucidate the role of inflammatory mediators in microcystin-LR-induced nephrotoxicity.
Main Methods:
- Rat peritoneal macrophages were stimulated with microcystin-LR, with or without pharmacological inhibitors (dexamethasone, quinacrine, thalidomide, cycloheximide).
- Supernatants were applied to an isolated perfused rat kidney model.
- Renal vascular resistance, glomerular filtration rate, and urinary flow were measured.
Main Results:
- Macrophage supernatants stimulated by microcystin-LR significantly increased renal vascular resistance, glomerular filtration rate, and urinary flow.
- Cycloheximide, quinacrine, and dexamethasone inhibited these effects.
- Thalidomide specifically blocked the increase in renal vascular resistance.
Conclusions:
- Macrophages stimulated by microcystin-LR release mediators that cause nephrotoxicity in the isolated perfused rat kidney.
- Phospholipase A(2), tumor necrosis factor-alpha (TNF-alpha), and other protein mediators are implicated in the renal toxic mechanism.
