c-mip Down-Regulates NF-κB Activity and Promotes Apoptosis in Podocytes

The mechanisms of podocyte disorders in cases of idiopathic nephrotic syndrome (INS) are complex and remain incompletely elucidated. The abnormal regulation of NF-kappa B may play a key role in the pathophysiology of these podocyte diseases, but at present, NF-kappa B has not been thoroughly investigated. In this study, we report that induction of c-mip in podocytes of patients with INS is associated with a down-regulation of RelA, a potent antiapoptotic factor that belongs to the NF-kappa B family. Overexpression of c-mip in differentiated podocytes promotes apoptosis by inducing caspase-3 activity and up-regulating the proapoptotic protein Bax, whereas the overall levels of the antiapoptotic protein Bcl-2 was concomitantly decreased. The associated overexpression of Rea prevented the proapoptotic effects of c-mip. In addition, the targeted induction of c-mip in podocytes in vivo inhibited the expression of the RelA protein and increased the Bax/Bcl-2 ratio. The expression of both c-mip and active caspase-3 increased in focal and segmental glomerulosclerosis biopsies, and both proteins displayed a dose spatial relationship. These results suggest that alterations in NF-kappa B activity might result from the up-regulation of c-mip and are likely to contribute to podocyte disorders in cases of INS. (Am J Pathol 2012, 180:2284-2292; http://dx.doi.org/10.1016/j.ajpath.2012.02.008)