Sterol Regulatory Element Binding Protein (SREBP)-1 is a novel regulator of the Transforming Growth Factor (TGF)-β receptor I (TβRI) through exosomal secretion.
Accumulation of matrix in the glomerulus is a classic hallmark of diabetic nephropathy. The profibrotic cytokine transforming growth factor beta 1 (TGF-β1) plays a central role in the development of glomerular sclerosis. Recent studies have demonstrated that the transcription factor sterol regulatory element binding protein (SREBP)-1 is an important regulator of glomerular sclerosis through both induction of TGF-β1 as well as facilitation of its signaling. Here we have identified that SREBP-1 is also a novel regulator of TGF-β receptor I (TβRI) expression in kidney mesangial cells. Inhibition of SREBP activation with fatostatin or downregulation of SREBP-1 using siRNA inhibited the expression of the receptor. SREBP-1 did not regulate TβRI transcription, nor did it induce its proteasomal or lysosomal degradation or proteolytic cleavage. Disruption of lipid rafts with cyclodextrin, however, prevented TβRI downregulation. This was not dependent on caveolae since SREBP-1 inhibition could induce TβRI downregulation in caveolin-1 knockout mesangial cells. SREBP-1 associated with TβRI, and SREBP-1 inhibition led to the secretion of TβRI in exosomes. Thus, we have identified a novel role for SREBP-1 as a cell surface retention factor for TβRI in mesangial cells, preventing its secretion in exosomes. Inhibition of SREBP-1 in vivo may thus provide a novel therapeutic strategy for diabetic nephropathy which targets multiple aspects of TGFβ signaling and matrix upregulation.
Division of Nephrology, McMaster University, L8N 3Z5, Hamilton, Canada.
Richard
R
Van Krieken
Division of Nephrology, McMaster University, L8N 3Z5, Hamilton, Canada.
Guang
G
Chen
Division of Nephrology, McMaster University, L8N 3Z5, Hamilton, Canada.
Bo
B
Gao
Division of Nephrology, McMaster University, L8N 3Z5, Hamilton, Canada.
Jolene
J
Read
Division of Nephrology, McMaster University, L8N 3Z5, Hamilton, Canada.
Hassan A
HA
Al Saleh
Division of Nephrology, McMaster University, L8N 3Z5, Hamilton, Canada.
Renzhong
R
Li
Division of Nephrology, McMaster University, L8N 3Z5, Hamilton, Canada.
Khalid
K
Al-Nedawi
Division of Nephrology, McMaster University, L8N 3Z5, Hamilton, Canada. Electronic address: krepinj@mcmaster.ca.
Joan C
JC
Krepinsky
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation; D055354:Exosomes / Q000378:metabolism*; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism; D018345:Mice, Knockout; D008954:Models, Biological; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D059748:Proteolysis; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D014158:Transcription, Genetic
D018125:Receptors, Transforming Growth Factor beta; D051780:Sterol Regulatory Element Binding Protein 1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat
Exosome; Kidney; SREBP-1; Transforming growth factor β; TβRI