YAP mediates the interaction between the Hippo and PI3K/Akt pathways in mesangial cell proliferation in diabetic nephrop
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ORIGINAL ARTICLE
YAP mediates the interaction between the Hippo and PI3K/Akt pathways in mesangial cell proliferation in diabetic nephropathy Xuan Qian1 · Linlin He1 · Meng Hao1 · Yuan Li1 · Xizhi Li1 · Yiqi Liu1 · Hong Jiang1 · Liu Xu1 · Chengcheng Li1 · Wenya Wu1 · Lei Du1 · Xiaoxing Yin1 · Qian Lu1 Received: 7 March 2020 / Accepted: 17 July 2020 © Springer-Verlag Italia S.r.l., part of Springer Nature 2020
Abstract 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. Keywords Diabetic nephropathy · Hippo pathway · Mesangial cells · Proliferation · YAP · PI3K Abbreviations BUN Blood urea nitrogen Cr Creatinine DN Diabetic nephropathy Xuan Qian, Linlin He and Meng Hao have contributed equally to this study. This article belongs to the topical collection Diabetic Nephropathy, managed by Giuseppe Pugliese. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00592-020-01582-w) contains supplementary material, which is available to authorized users. * Qian Lu [email protected] 1
ECM Extracellular matrix FBG Fasting blood glucose Lats1/2 Large tumour suppressor 1/2 serine/threonine protein kinases MC Mesangial cell MOB1 Mps-one binder 1 MST1/2 Module consists of Ste20-like serine/threonine kinases 1/2 PAS Periodic acid Schiff PI3K Phosphoinositide-3-kinase TAZ Transcriptional co-activator with PDZ binding motif TBST Tris-buffered saline with Tween TEAD TEA domain YAP Yes-associated pr
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