Aims/hypothesis Translationally controlled tumour protein (TCTP) is thought to be involved in cell growth by regulating mTOR complex 1 (mTORC1) signalling. As diabetes characteristically induces podocyte hypertrophy and mTORC1 has been implicated in this process, TCTP may have a role in the pathogenesis of diabetes-induced podocyte hypertrophy. Methods We investigated the effects and molecular mechanisms of TCTP in diabetic mice and in high glucose-stimulated cultured podocytes. To characterise the role of TCTP, we conducted lentivirus-mediated gene silencing of TCTP both in vivo and in vitro. Results Glomerular production of TCTP was significantly higher in streptozotocin induced-diabetic DBA/2J mice than in control animals. Double-immunofluorescence staining for TCTP and synaptopodin revealed that podocyte was the principal cell responsible for this increase. TCTP knockdown attenuated the activation of mTORC1 downstream effectors and the overproduction of cyclin-dependent kinase inhibitors (CKIs) in diabetic glomeruli, along with a reduction in proteinuria and a decrease in the sizes of podocytes as well as glomeruli. In addition, knockdown of TCTP in db/db mice prevented the development of diabetic nephropathy, as indicated by the amelioration of proteinuria, mesangial expansion, podocytopenia and glomerulosclerosis. In accordance with the in vivo data, TCTP inhibition abrogated high glucose-induced hypertrophy in cultured podocytes, which was accompanied by the downregulation of mTORC1 effectors and CKIs. Conclusions/interpretation These findings suggest that TCTP might play an important role in the process of podocyte hypertrophy under diabetic conditions via the regulation of mTORC1 activity and the induction of cell-cycle arrest.
Bibliographical noteFunding Information:
Funding This work was supported in part by the Brain Korea 21 Project for Medical Sciences, Yonsei University, by the Korean Science and Engineering Foundation grant funded by the Korean government (R01-2007-000-20263-0), and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0030711).
All Science Journal Classification (ASJC) codes
- Internal Medicine
- Endocrinology, Diabetes and Metabolism