SREBP-1 Mediates Angiotensin II-Induced TGF-β1 Upregulation and Glomerular Fibrosis.
Angiotensin II is an important mediator of CKD of diverse etiology. A common pathologic feature of CKD is glomerular fibrosis, a central mediator of which is the profibrotic cytokine TGF-β. The mechanisms underlying the induction of TGF-β and matrix by angiotensin II are not completely understood. Recent studies showed that overexpression of the transcription factor SREBP-1 induces glomerular sclerosis and that angiotensin II can activate SREBP-1 in tubular cells. We thus studied whether SREBP-1 is activated by angiotensin II and mediates angiotensin II-induced profibrogenic responses in primary rat mesangial cells. Treatment of cells with angiotensin II induced the upregulation and activation of SREBP-1. Angiotensin II-induced activation of SREBP-1 required signaling through the angiotensin II type I receptor and activation of PI3K/Akt in addition to the chaperone SCAP and protease S1P. Notably, angiotensin II-induced endoplasmic reticulum stress was identified as a key mediator of Akt-SREBP-1 activation, and inhibition of endoplasmic reticulum stress or SREBP-1 prevented angiotensin II-induced SREBP-1 binding to the TGF-β promoter, TGF-β upregulation, and downstream fibronectin upregulation. Endoplasmic reticulum stress alone, however, did not induce TGF-β upregulation despite activating SREBP-1. Although not required for SREBP-1 activation by angiotensin II, EGF receptor signaling was necessary for activation of the SREBP-1 cotranscription factor Sp1, which provided a required second signal for TGF-β upregulation. In vivo, endoplasmic reticulum stress and SREBP-1-dependent effects were induced in glomeruli of angiotensin II-infused mice, and administration of the SREBP inhibitor fatostatin prevented angiotensin II-induced TGF-β upregulation and matrix accumulation. SREBP-1 and endoplasmic reticulum stress thus provide potential novel therapeutic targets for the treatment of CKD.
Division of Nephrology, McMaster University, Hamilton, Ontario, Canada.
Tony N
TN
Wang
Division of Nephrology, McMaster University, Hamilton, Ontario, Canada.
Xing
X
Chen
Division of Nephrology, McMaster University, Hamilton, Ontario, Canada.
Renzhong
R
Li
Division of Nephrology, McMaster University, Hamilton, Ontario, Canada.
Bo
B
Gao
Division of Nephrology, McMaster University, Hamilton, Ontario, Canada.
Zahraa
Z
Mohammed-Ali
Division of Nephrology, McMaster University, Hamilton, Ontario, Canada.
Chao
C
Lu
Division of Nephrology, McMaster University, Hamilton, Ontario, Canada.
Victoria
V
Yum
Division of Nephrology, McMaster University, Hamilton, Ontario, Canada.
Jeffrey G
JG
Dickhout
Division of Nephrology, McMaster University, Hamilton, Ontario, Canada krepinj@mcmaster.ca.
Joan C
JC
Krepinsky
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D066246:ErbB Receptors / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis; D005355:Fibrosis; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000473:pathology; D057057:Serine Proteases / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D013844:Thiazoles; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation
D005353:Fibronectins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; C102196:SREBP cleavage-activating protein; D016329:Sp1 Transcription Factor; D051780:Sterol Regulatory Element Binding Protein 1; D013844:Thiazoles; D053773:Transforming Growth Factor beta1; C545733:fatostatin; D000804:Angiotensin II; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D057057:Serine Proteases
TGF-β; angiotensin; cell signaling; chronic kidney disease; fibrosis