Nitric oxide is an important mediator of renal tubular epithelial cell death in vitro and in murine experimental hydronephrosis.
Macrophages play a pivotal role in tissue injury and fibrosis during renal inflammation. Although macrophages may induce apoptosis of renal tubular epithelial cells, the mechanisms involved are unclear. We used a microscopically quantifiable co-culture assay to dissect the cytotoxic interaction between murine bone marrow-derived macrophages and Madin-Darby canine kidney cells and primary murine renal tubular epithelial cells. The induction of tubular cell apoptosis by cytokine-activated macrophages was reduced by inhibitors of nitric oxide synthase whereas tubular cell proliferation was unaffected. Furthermore, cytokine-activated macrophages derived from mice targeted for the deletion of inducible nitric oxide synthase were noncytotoxic. We then examined the role of nitric oxide in vivo by inhibiting inducible nitric oxide synthase in the model of murine experimental hydronephrosis. l-N(6)-(1-iminoethyl)-lysine was administered in the drinking water between days 5 and 7 after ureteric obstruction. Macrophage infiltration was comparable between groups, but treatment significantly inhibited tubular cell apoptosis at day 7. Tubular cell proliferation was unaffected. Inducible nitric oxide synthase blockade also reduced interstitial cell apoptosis and increased collagen III deposition. These data indicate that nitric oxide is a key mediator of macrophage-directed tubular cell apoptosis in vitro and in vivo and also modulates tubulointerstitial fibrosis.
Kipari
Tiina
T
Phagocyte Laboratory, Medical Research Council Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh, Scotland.
Cailhier
Jean-Francois
JF
Ferenbach
David
D
Watson
Simon
S
Houlberg
Kris
K
Walbaum
David
D
Clay
Spike
S
Savill
John
J
Hughes
Jeremy
J
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D005355:Fibrosis / Q000473:pathology; D006869:Hydronephrosis / Q000139:chemically induced*; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D009395:Nephritis, Interstitial / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors
D016207:Cytokines; C090663:N(6)-(1-iminoethyl)lysine; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D008239:Lysine