Changes in the distribution of tenascin and fibronectin in the mouse ovary during folliculogenesis, atresia, corpus luteum formation and luteolysis.

Tenascin and fibronectin are components of the extracellular matrices that oppose and promote adhesion, respectively. Using immunohistochemical techniques, we studied the distribution of tenascin and fibronectin in the mouse ovary, in which dynamic reconstruction and degeneration occur during folliculogenesis, atresia, ovulation, corpus luteum formation and luteolysis. In growing follicles, tenascin was only detected in the theca externa layer, while fibronectin was detected in the theca externa layer, theca interna layer and basement membrane. During follicular atresia, granulosa cells, which are surrounded by the basement membrane, began to die through apoptosis. In atretic follicles, tenascin was detected in the basement membrane and theca externa layer. Distribution of fibronectin in atretic follicles was similar to that in healthy growing follicles, except that granulosa cells were slightly immunopositive for fibronectin. In young corpus luteum, luteal cells exhibit high 3 beta -hydroxysteroid dehydrogenase (3 beta -HSD) activity, an enzyme indispensable for progesterone production. Tenascin was barely detected in young luteal cells. 3 beta -HSD activity in luteal cells declines with corpus luteum age, and in older corpus luteum there is an increase in apoptotic death of luteal cells. Tenascin was intensely immunopositive in old luteal cells.In contrast, fibronectin immunostaining in luteal cells was relatively constant during corpus luteum formation and luteolysis. Our observations suggest that tenascin is critical in controlling the degenerative changes of tissues in mouse ovaries. Moreover, in all circumstances observed in this study, tenascin always co-localized with fibronectin, suggesting fibronectin is indispensable for the function of tenascin.

Mizoribine corrects defective nephrin biogenesis by restoring intracellular energy balance.

Proteins are modified and folded within the endoplasmic reticulum (ER). When the influx of proteins exceeds the capacity of the ER to handle the load, the ER is "stressed" and protein biogenesis is affected. We have previously shown that the induction of ER stress by ATP depletion in podocytes leads to mislocalization of nephrin and subsequent injury of podocytes. The aim of the present study was to determine whether ER stress is associated with proteinuria in vivo and whether the immunosuppressant mizoribine may exert its antiproteinuric effect by restoring normal nephrin biogenesis. Induction of nephrotic-range proteinuria with puromycin aminonucleoside in mice increased expression of the ER stress marker GRP78 in podocytes, and led to the mislocalization of nephrin to the cytoplasm. In vitro, mizoribine, through a mechanism likely dependent on the inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) activity in podocytes, restored the intracellular energy balance by increasing levels of ATP and corrected the posttranslational processing of nephrin. Therefore, we speculate that mizoribine may induce remission of proteinuria, at least in part, by restoring the biogenesis of slit diaphragm proteins in injured podocytes. Further understanding of the ER microenvironment may lead to novel approaches to treat diseases in which abnormal handling of proteins plays a role in pathogenesis.