SREBP-1 Mediates Angiotensin II-Induced TGF-β1 Upregulation and Glomerular Fibrosis

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-b. The mechanisms underlying the induction of TGF-b 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-b promoter, TGF-b upregulation, and downstream fibronectin upregulation. Endoplasmic reticulum stress alone, however, did not induce TGF-b 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-b 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-b upregulation and matrix accumulation. SREBP-1 and endoplasmic reticulum stress thus provide potential novel therapeutic targets for the treatment of CKD.

Asymmetric dimethylarginine (ADMA) treatment induces apoptosis in cultured rat mesangial cells via endoplasmic reticulum stress activation

“…However, although AEBSF treatment effectively diminished ATF6 cleavage, it is noteworthy that AEBSF is a non‐specific ATF6 inhibitor. S1P also facilitates cleavage of other proteins such as sterol regulatory element‐binding protein, which is associated with mesangial cell dysfunction (Wang et al, ). Although several recent studies have revealed that ATF6 activation induces apoptotic cell death in various cells (Han et al, ; Hirsch et al, ), further study is needed to reveal the precise role of ATF6 in mesangial cells.…”

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…Specifically, CHOPϪ/Ϫ mice are protected from ANG IIinduced NADPH oxidase activation, hypertension, and cardiovascular pathology (464). ANG II-induced ER stress exists downstream of the ADAM17/EGFR transactivation cascade (1034,1035) and stromal interaction molecule 1 (STIM1) induction (464), and upstream of cardiac (465) and renal TGF-␤ induction (1118), vascular apoptotic pathway (989), and brain SFO NF-B activation (1218). While these studies suggest that ER stress is vital for ANG II-induced signal transduction and pathologies, it remains elusive whether AT 1 R stimulation increases unfolded proteins in ER, or if so, how it happens.…”

“…Moreover, EGFR transactivation by ANG II in renal proximal tubule appears critical for ANG II-induced renal TGF-␤ induction, epithelial cell-mesenchymal cell transition, and fibrosis (150,151). In addition to EGFR, a recent study demonstrated that ER stress-induced activation of a transcription factor sterol regulatory elementbinding protein-1 (SREBP-1) contributes to TGF-␤ induction and renal fibrosis in ANG II-infused mice (1118).…”

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

“…De novo lipogenesis mediated by SREBP-1 has been described as a new mediator of TGF-β1 signaling pathway, thus its activation plays a key role in the progression of inflammation and glomerular fibrosis in this cell type under diabetic conditions [110][111][112].…”