Resumen de Depressed adrenomedullin in the embryonic transforming growth factor-ß1 null mouse becomes elevated postnatally

Alfredo Martínez, Laurent L. Ozbun, Mercedes Garayoa, Luis Montuenga Badía, John J. Letterio, Sonia B. Jakowlew, Elena Bodegas Frías

• Transforming growth factor-beta (TGF-b) and adrenomedullin are multifunctional regulatory proteins which are expressed in developing embryonic and adult tissues. Because of their colocalization, TGF-b1 and adrenomedullin may be able to coordinately act to influence development and differentiation. In order to learn more about the biology of adrenomedullin in the absence of the effects of TGF-b1 in vivo, we examined adrenomedullin in the TGF-b1 null mouse. A generally lower amount of adrenomedullin was detected by immunohistochemical staining analysis in multiple tissues from embryonic TGF-b1 null mice compared to wildtype animals, including the heart, lung, brain, liver, and kidney, among others. In contrast, immunohistochemical staining for adrenomedullin was more intense in tissues of the postnatal TGF-b1 null mouse compared to the wildtype mouse. These observations were confirmed by quantitative real time RT-PCR for adrenomedullin in both embryos and postnatal animals, as well as in cultured mouse embryo fibroblasts from TGF-b1 null and wildtype mice. In addition, when cultured mouse embryo fibroblasts were treated with a neutralizing monoclonal antibody against TGF-b1, the levels of adrenomedullin expression were statistically reduced compared to untreated cells. Our data show that expression of adrenomedullin is reduced in tissues of the developing embryonic TGF-b1 null mouse compared to the wildtype mouse, but increases during postnatal development in TGF-b1 null mice. The elevated expression of adrenomedullin which occurs postnatally in the TGF-b1 null mouse may be a cause or a consequence of the multifocal wasting syndrome which is characteristic of postnatal TGF-b1 null mice.