| First Author | Uttarwar L | Year | 2012 |
| Journal | Am J Physiol Renal Physiol | Volume | 302 |
| Issue | 3 | Pages | F329-41 |
| PubMed ID | 22031849 | Mgi Jnum | J:180245 |
| Mgi Id | MGI:5305896 | Doi | 10.1152/ajprenal.00136.2011 |
| Citation | Uttarwar L, et al. (2012) SREBP-1 activation by glucose mediates TGF-beta upregulation in mesangial cells. Am J Physiol Renal Physiol 302(3):F329-41 |
| abstractText | Glomerular matrix accumulation is a hallmark of diabetic nephropathy. Recent studies showed that overexpression of the transcription factor sterol-responsive element-binding protein (SREBP)-1 induces pathology reminiscent of diabetic nephropathy, and SREBP-1 upregulation was observed in diabetic kidneys. We thus studied whether SREBP-1 is activated by high glucose (HG) and mediates its profibrogenic responses. In primary rat mesangial cells, HG activated SREBP-1 by 30 min, seen by the appearance of its cleaved nuclear form (nSREBP-1), EMSA, and by activation of an SREBP-1 response element (SRE)-driven green fluorescent protein construct. Activation was dose dependent and not induced by an osmotic control. Site 1 protease was required, since its inhibition by AEBSF prevented SREBP-1 activation. SCAP, the ER-associated chaperone for SREBP-1, was also necessary since its inhibitor fatostatin also blocked SREBP-1 activation. Signaling through the EGFR/phosphatidylinositol 3-kinase (PI3K) pathway, which we previously showed mediates HG-induced TGF-beta1 upregulation, and through RhoA, were upstream of SREBP-1 activation (Wu D, Peng F, Zhang B, Ingram AJ, Gao B, Krepinsky JC. Diabetologia 50: 2008-2018, 2007; Wu D, Peng F, Zhang B, Ingram AJ, Kelly DJ, Gilbert RE, Gao B, Krepinsky JC. J Am Soc Nephrol 20: 554-566, 2009). Fatostatin and AEBSF prevented HG-induced TGF-beta1 upregulation by Northern blot analysis, and HG-induced TGF-beta1 promoter activation was inhibited by both fatostatin and dominant negative SREBP-1a. Chromatin immunoprecipitation analysis confirmed that HG led to SREBP-1 binding to the TGF-beta1 promoter in a region containing a putative SREBP-1 binding site (SRE). Thus HG-induced SREBP-1 activation requires EGFR/PI3K/RhoA signaling and SCAP-mediated transport to the Golgi for its proteolytic cleavage. Activated SREBP-1 binds to the TGF-beta promoter, resulting in TGF-beta1 upregulation in response to HG. SREBP-1 thus provides a potential novel therapeutic target for the treatment of diabetic nephropathy. |
