THE ROLE OF STEROL REGULATORY ELEMENT BINDING PROTEIN (SREBP) IN KIDNEY FIBROSIS

Abstract

<p>There has been a steady increase in the number of patients with chronic kidney disease. The etiology has been linked to excessive fibrosis progression until the kidney function becomes compromised. We are investigating tubulointerstitial fibrosis (TIF) specifically, as it correlates strongly with the decline of renal function.</p> <p>In our study we investigated the role that active SREBP may play in apoptosis and fibrosis in vivo and in vitro. Treating HK-2 cells with TNFα resulted in the cleavage of SREBP and activation of its SRE promoter. By utilizing a number of inhibitors, we found TNFα induced SREBP cleavage through both a caspase independent and dependent manner.</p> <p>We used fatostatin, a SCAP inhibitor, to reduce the amount of active SREBP in animals in the unilateral ureter obstruction (UUO) model. This model is well known for its development of TIF. Fatostatin decreased SREBP-1 and SREBP-2 activation in mice after 7 and 14 days. Fatostatin increased glomerulotubular integrity and proximal tubular mass as evaluated using lectin staining, along with reducing the number of cells undergoing apoptosis as evaluated by TUNEL staining. Using the Masson Trichrome, Picrosirius red and fibronectin staining, we found a reduction of fibrosis. Fatostatin was also found to attenuate the accumulation of infiltrating myofibroblasts and T cells. These results point to a pathological role for SREBP in TIF.</p>