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The PI3-Kinase-Akt Pathway Promotes Mesangial Cell Survival and Inhibits Apoptosis In Vitro via NF-κB and Bad

2003; American Society of Nephrology; Volume: 14; Issue: 6 Linguagem: Inglês

10.1097/01.asn.0000066140.99610.32

1533-3450

Haruko Shimamura, Yoshio Terada, Tomokazu Okado, Hiroyuki Tanaka, Seiji Inoshita, Sei Sasaki,

Cancer-related molecular mechanisms research

While the serine/threonine protein kinase Akt has attracted attention as a mediator of survival (anti-apoptotic) signal, the regulation and function of the PI3-kinase-Akt pathway in mesangial cells is not well known. To explore the significance of the PI3-kinase-Akt pathway, this study used PI3-kinase inhibitors (Wortmannin and LY294002) and recombinant adenoviruses encoding a dominant-active mutant of Akt (AxCAmyrAkt) and a dominant-negative mutant of Akt (AxCAAkt-AA) in cultured rat mesangial cells. Apoptotic signals were measured by nucleosomal laddering of DNA, caspase 3 assay, and cell death detection ELISA. The PI3 kinase inhibitors and dominant-negative mutant of Akt increased the apoptotic signals in the presence of platelet-derived growth factor (PDGF), while the dominant-active mutant of Akt prevented apoptosis induced by a serum-free medium. In separate experiments, we further investigated downstream signals of Akt in mesangial cells. While PDGF activated NF-kappa B and phosphorylated Bad, these reactions were inhibited by overexpression of the dominant-negative mutant of Akt as well as the PI3-kinase inhibitors. These data indicate, firstly, that Akt is phosphorylated by PDGF, and secondly, that the activated Akt prevents apoptotic changes via activation of NF-kappa B and phosphorylation of Bad in mesangial cells. This study investigated whether it is Bad phosphorylation or NF-kappa B activation that provides the anti-apoptotic effects of Akt, and the data suggested that NF-kappa B is probably the principal contributor to the downstream activation of the PI3-kinase-Akt pathway. The findings suggest that the PI3-kinase-Akt pathway acts as a survival signal and plays a key role in the regulation of apoptotic change in mesangial cells principally via NF-kappa B.