title: Reduction of renal mass is lethal in mice lacking vimentin. Role of endothelin-nitric oxide imbalance.
abstract: Modulation of vascular tone by chemical and mechanical stimuli is a crucial adaptive phenomenon which involves cytoskeleton elements. Disruption, by homologous recombination, of the gene encoding vimentin, a class III intermediate filament protein mainly expressed in vascular cells, was reported to result in apparently normal phenotype under physiological conditions. In this study, we evaluated whether the lack of vimentin affects vascular adaptation to pathological situations, such as reduction of renal mass, a pathological condition which usually results in immediate and sustained vasodilation of the renal vascular bed. Ablation of 3/4 of renal mass was constantly lethal within 72 h in mice lacking vimentin (Vim-/-), whereas no lethality was observed in wild-type littermates. Death in Vim-/- mice resulted from end-stage renal failure. Kidneys from Vim-/- mice synthesized more endothelin, but less nitric oxide (NO), than kidneys from normal animals. In vitro, renal resistance arteries from Vim-/- mice were selectively more sensitive to endothelin, less responsive to NO-dependent vasodilators, and exhibited an impaired flow (shear stress)- induced vasodilation, which is NO dependent, as compared with those from normal littermates. Finally, in vivo administration of bosentan, an endothelin receptor antagonist, totally prevented lethality in Vim-/- mice. These results suggest that vimentin plays a key role in the modulation of vascular tone, possibly via the tuning of endothelin-nitric oxide balance.
authors.affiliation: INSERM U 380, Institut Cochin de Génétique Moléculaire, Paris, France. terzi@cochin.inserm.fr
authors.forename: F
authors.initials: F
authors.lastname: Terzi
authors.forename: D
authors.initials: D
authors.lastname: Henrion
authors.forename: E
authors.initials: E
authors.lastname: Colucci-Guyon
authors.forename: P
authors.initials: P
authors.lastname: Federici
authors.forename: C
authors.initials: C
authors.lastname: Babinet
authors.forename: B I
authors.initials: BI
authors.lastname: Levy
authors.forename: P
authors.initials: P
authors.lastname: Briand
authors.forename: G
authors.initials: G
authors.lastname: Friedlander
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D015152:Blotting, Northern; D000077300:Bosentan; D003404:Creatinine / Q000097:blood; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D009252:NADPH Dehydrogenase / Q000378:metabolism; D009392:Nephrectomy / Q000379:methods; D009569:Nitric Oxide / Q000502:physiology*; D019335:Nitroarginine / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D013449:Sulfonamides / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D014746:Vimentin / Q000172:deficiency* / Q000235:genetics
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D014746:Vimentin; D009599:Nitroprusside; D019335:Nitroarginine; D009569:Nitric Oxide; D015240:Phorbol 12,13-Dibutyrate; D003404:Creatinine; D009252:NADPH Dehydrogenase; D000109:Acetylcholine; D000077300:Bosentan; D007213:Indomethacin