AIMS: Glomerular mesangial cell (MC) proliferation is one of the main pathological changes in diabetic nephropathy (DN), but its mechanism needs further elaboration. The Hippo and PI3K/Akt signalling pathways are involved in the regulation of MC proliferation, but their relationship in hyperglycaemia-induced MC proliferation has not been reported. METHODS: We used db/db mice and high-glucose-cultured mesangial cells to generate a diabetic nephropathy model. An MST1-knockdown plasmid was used to identify whether the PI3K/Akt pathway is linked to the Hippo pathway through MST1. LY294002 and SC79 were used to verify the role of the PI3K/Akt signalling pathway in MC cells. RNA silencing and overexpression were performed by using YAP and PTEN-expression/knockdown plasmids to investigate the function of YAP and PTEN, respectively, in the Hippo and PI3K/Akt signalling pathways. RESULTS: By examining a potential feedback loop, we found decreased phosphorylation of MST1 and Lats1 and increased PI3K/Akt activation in db/db mice and high glucose-treated MCs, along with increased MC proliferation. The results of our gene silencing experiment proved PI3K/Akt-mediated intervention in the Hippo pathway and the regulatory effect of YAP on PI3K/Akt through PTEN. CONCLUSIONS: The Hippo pathway is inhibited under diabetic conditions, leading to YAP activation and promoting MC proliferation. The PI3K/Akt pathway is activated through the inhibitory effect of YAP on its repressor, PTEN. Finally, activation of the PI3K/Akt pathway inhibits the Hippo pathway, resulting in nuclear YAP accumulation and accelerating MC proliferation and DN formation.
AIMS: Glomerular mesangial cell (MC) proliferation is one of the main pathological changes in diabetic nephropathy (DN), but its mechanism needs further elaboration. The Hippo and PI3K/Akt signalling pathways are involved in the regulation of MC proliferation, but their relationship in hyperglycaemia-induced MC proliferation has not been reported. METHODS: We used db/db mice and high-glucose-cultured mesangial cells to generate a diabetic nephropathy model. An MST1-knockdown plasmid was used to identify whether the PI3K/Akt pathway is linked to the Hippo pathway through MST1. LY294002 and SC79 were used to verify the role of the PI3K/Akt signalling pathway in MC cells. RNA silencing and overexpression were performed by using YAP and PTEN-expression/knockdown plasmids to investigate the function of YAP and PTEN, respectively, in the Hippo and PI3K/Akt signalling pathways. RESULTS: By examining a potential feedback loop, we found decreased phosphorylation of MST1 and Lats1 and increased PI3K/Akt activation in db/db mice and high glucose-treated MCs, along with increased MC proliferation. The results of our gene silencing experiment proved PI3K/Akt-mediated intervention in the Hippo pathway and the regulatory effect of YAP on PI3K/Akt through PTEN. CONCLUSIONS: The Hippo pathway is inhibited under diabetic conditions, leading to YAP activation and promoting MC proliferation. The PI3K/Akt pathway is activated through the inhibitory effect of YAP on its repressor, PTEN. Finally, activation of the PI3K/Akt pathway inhibits the Hippo pathway, resulting in nuclear YAP accumulation and accelerating MC proliferation and DN formation.
Authors: Sang Hoon Kim; Young Woo Jang; Patrick Hwang; Hyun Jung Kim; Gi Yeon Han; Chan Wha Kim Journal: Exp Mol Med Date: 2012-01-31 Impact factor: 8.718
Authors: M A St John; W Tao; X Fei; R Fukumoto; M L Carcangiu; D G Brownstein; A F Parlow; J McGrath; T Xu Journal: Nat Genet Date: 1999-02 Impact factor: 38.330