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SREBP-1 Mediates Angiotensin II-Induced TGF-β1 Upregulation and Glomerular Fibrosis.
- Source :
-
Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2015 Aug; Vol. 26 (8), pp. 1839-54. Date of Electronic Publication: 2014 Nov 14. - Publication Year :
- 2015
-
Abstract
- 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.<br /> (Copyright © 2015 by the American Society of Nephrology.)
- Subjects :
- Animals
Cells, Cultured
ErbB Receptors metabolism
Fibronectins biosynthesis
Fibrosis
Intracellular Signaling Peptides and Proteins metabolism
Kidney pathology
Male
Membrane Proteins metabolism
Mice
Mice, Inbred C57BL
Phosphatidylinositol 3-Kinases metabolism
Proto-Oncogene Proteins c-akt metabolism
Pyridines
Rats, Inbred Dahl
Rats, Sprague-Dawley
Receptor, Angiotensin, Type 1 metabolism
Renal Insufficiency, Chronic pathology
Serine Proteases metabolism
Sp1 Transcription Factor metabolism
Thiazoles
Transforming Growth Factor beta1 metabolism
Up-Regulation
Angiotensin II metabolism
Endoplasmic Reticulum Stress
Mesangial Cells metabolism
Renal Insufficiency, Chronic metabolism
Sterol Regulatory Element Binding Protein 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1533-3450
- Volume :
- 26
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of the American Society of Nephrology : JASN
- Publication Type :
- Academic Journal
- Accession number :
- 25398788
- Full Text :
- https://doi.org/10.1681/ASN.2013121332