ID1 inhibits USF2 and blocks TGF-ß-induced apoptosis in mesangial cells.

Mesangial cells (MC) play an essential role in normal function of the glomerulus. Phenotypic changes in MC lead to the development of glomerular diseases such as diabetic nephropathy and glomerulosclerosis. The late phase of diabetic glomerulopathy is characterized by MC death and fibrosis. Current data highlight the transforming growth factor (TGF)-ß as a trigger of the pathological changes observed in MC, including death by apoptosis. However, the mechanisms and mediators involved in this process are still poorly understood. Identification of novel elements involved in MC death may provide a better understanding of the pathophysiology of glomerular diseases. Here, we show that bone morphogenetic proteins (BMPs; known antagonists of the profibrotic effects of TGF-ß in the kidney) strongly induce inhibitor of DNA binding (ID1) mRNA transcription and protein expression in human MC. ID genes have been implicated in cell survival control and are constitutively expressed in MC. We show that BMPs and ID1 exert an anti-apoptotic effect in MC by inhibition of USF2 transcriptional activity. On the other hand, TGF-ß upregulates USF2, increasing BAX (proapoptotic gene) levels and apoptosis rates. Taken together, our results point to a novel molecular pathway that modulates MC apoptosis, which is potentially involved in the pathogenesis of glomerular diseases.

Disrupted cell cycle control in cultured endometrial cells from patients with endometriosis harboring the progesterone receptor polymorphism PROGINS.

Presently, little is understood about how endometriosis is established or maintained, or how genetic factors can predispose women to the disease. Because of the crucial role that the progesterone receptor polymorphism PROGINS plays in predisposing women to the development of endometriosis, we hypothesized that this variant may influence critical steps during endometrial cell metabolism that are involved in the pathogenesis of endometriosis. Eutopic endometria were collected from three sources: women with endometriosis who had a single PROGINS allele (from the progesterone receptor gene); women with endometriosis who had the wild-type progesterone receptor allele; and women without endometriosis who had the wild-type allele. Cells prepared from the eutopic endometria of these women were stimulated with both estradiol and progesterone, and then examined for cell proliferation, viability, and apoptosis. The cells from women with endometriosis that carried the PROGINS allele demonstrated increased proliferation, greater viability, and decreased apoptosis following progesterone treatment. In general, these parameters were very different as compared with those of women with endometriosis but without the PROGINS allele and women in the control group. This result indicates there is a reduced level of progesterone responsiveness in women who carry the PROGINS polymorphism. Because progesterone responsiveness is known to be an important characteristic of women with endometriosis, these data support the contention that the PROGINS polymorphism enhances the endometriosis phenotype.