Translationally controlled tumour protein is associated with podocyte hypertrophy in a mouse model of type 1 diabetes.
OBJECTIVE
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
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.
Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
D K
DK
Kim
B Y
BY
Nam
J J
JJ
Li
J T
JT
Park
S H
SH
Lee
D H
DH
Kim
J Y
JY
Kim
H Y
HY
Kang
S H
SH
Han
T H
TH
Yoo
D S
DS
Han
S W
SW
Kang
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D049108:Cell Enlargement; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D020868:Gene Silencing; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D046912:Multiprotein Complexes; D050199:Podocytes / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D000090324:Tumor Protein, Translationally-Controlled 1
D014408:Biomarkers, Tumor; D008840:Microfilament Proteins; D046912:Multiprotein Complexes; D011506:Proteins; C503968:Synpo protein, mouse; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases