<p>End stage renal disease (ESRD) has been a world-wide cause of renal disease-related fatality. Most patients with ESRD progress through chronic kidney disease (CKD). There are various causes of CKD including mechanical stress, infections, high blood pressure or immune conditions. Renal fibrosis is known to play an important pathogenic role in CKD and ESRD. Transforming growth factor-beta (TGF-ß) is one of the major mediators of fibrosis, and inhibition of TGF-ß could reduce renal fibrosis in in vitro models. One of the well - known inducers of TGF-ß transcr iption is Angiotensin II (ANGII). 1 This is a major contributor to the matrix accumulation and glomerular fibrosis leading to a decline in kidney function and kidney failure in patients with chronic kidney disease (CKD). 2 A recent study demonstrated that TGF -ß could be increased by SREBP -1c overexpression. 3 My laboratory’ s data showed that ANGII could induce TGF-ß on a transcriptional level, and this induction could be block ed by Fatostatin, an SREBP/SCAP inhibitor. My data showed that ANGII could induce SREBP-1 in a time and dose dependent manner. Therefore my study focused on understanding the role of SREBP-1 in ANGII-induced TGF-ß upregulation in primary mesangial cells (MCs). We found that ANGII- induced TGF-ß promoter activity requires Angiotensin type 1 receptor (AT1R) and SREBP-1 activation as well as ER stress. Interestingly , the activation of SREBP-1 by ANGII stimulation relies on ER stress and PI3K/AKT signaling. Both ANGII and ER stress inducer s could induce AKT phosphorylation, indicat ing that ER stress is an upstream mediator in th is signaling pathway. We also found that ER stress inhibit ion could block SREBP-1 activation by ANGII stimulation and, more importantly , could also block ANGII- induced TGF-ß promoter activity. In C57BL/6 mice infused with ANGII for one week, we found that both SREBP-1 and GRP78 were significantly upregulated in glomeruli in the ANGII infusion group compared with the control group. Taken together , this data indicates that ER stress is required for SREBP-1 activation, both of which are mediators of kidney fibrosis.</p> / Master of Science (MSc)