REDUCTION OF RENAL MASS IS LETHAL IN MICE LACKING VIMENTIN - ROLE OF ENDOTHELIN NITRIC-OXIDE IMBALANCE

Modulation of vascular tone by chemical and mechanical stimuli is a cr ucial adaptive phenomenon which involves cytoskeleton elements. Disrup tion, by homologous recombination, of the gene encoding vimentin, a cl ass III intermediate filament protein mainly expressed in vascular cel ls, was reported to result in apparently normal phenotype under physio logical conditions. In this study, we evaluated whether the lack of vi mentin affects vascular adaptation to pathological situations, such as reduction of renal mass, a pathological condition which usually resul ts in immediate and sustained vasodilation of the renal vascular bed. Ablation of 3/4 of renal mass was constantly lethal within 72 h in mic e lacking vimentin (Vim(-/-)), whereas no lethality was observed in wi ld-type littermates. Death in Vim(-/-) mice resulted from end-stage re nal failure. Kidneys from Vim(-/-) mice synthesized more endothelin, b ut less nitric oxide (NO), than kidneys from normal animals. In vitro, renal resistance arteries from Vim(-/-) mice were selectively more se nsitive to endothelin, less responsive to NO-dependent vasodilators, a nd exhibited an impaired flow (shear stress)induced vasodilation, whic h is NO dependent, as compared with those from normal littermates, Fin ally, in vivo administration of bosentan, an endothelin receptor antag onist, totally prevented lethality in vim(-/-) mice. These results sug gest that vimentin plays a key role in the modulation of vascular tone , possibly via the tuning of endothelin-nitric oxide balance.