PST3.1A, AN INHIBITOR OF MGAT5 DECREASES RENAL FIBROSIS IN A RAT MODEL OF CHRONIC KIDNEY DISEASE

Abstract BACKGROUND AND AIMS Renal fibrosis is a main feature of chronic kidney disease (CKD) that participates in its progression to the end stage.(1) N-acetylglucosaminyltransferase 5 (MGAT5) adds N-acetylglucosamines to newly synthesized glycoproteins and is overexpressed in tumors participating in epithelial–mesenchymal transition (EMT), invasion and cell migration, some of the features observed in fibrosis.(2) PST3.1a is an inhibitor of MGAT5 that has already been shown to be beneficial in the treatment of brain tumors.(3) We presently evaluated the use of PST3.1a on renal fibrosis in CKD. METHOD Six-week-old Sprague-Dawley rats underwent 5/6th subtotal nephrectomy (SNx) (n = 16) or no surgery (Control) (n = 14). PST3.1a (0.2 mg/mL) or placebo was administered in the drinking water from the day of surgery for the entire protocol. Animals were sacrificed 4 weeks after surgery and the kidney was taken to evaluate fibrosis, MGAT5 expression and activity. Fibrosis was determined both by Sirius red staining and by immunohistochemistry (IHC) staining of three types of collagen (I, III and IV). To measure the activity of MGAT5 immunohistochemistry staining of Phaseolus Vulgaris Leucoagglutinine (PHA-L) and galectin 3 were carried out. RESULTS MGAT5 expression (12.2% ± 1.2 control versus 26.7% ± 2.6 SNx) and renal fibrosis (11.5% ± 0.7 control versus 26.9% ± 1.9 SNx) increased significantly in SNx animals in a preliminary study. In the present study, PST3.1atreatment significantly decreased the expression of collagen 1 (col1) (2.1% ± 0.2 SNx versus 1.3% ± 0.2 SNx + PST3.1a; P < 0.05) and collagen 4 (col4) (9.4% ± 1.01 SNx versus 6.4% ± 0.3SNx + PST3.1a; P < 0.05) in kidneys of SNx animals (Fig. 1). Collagen 3 also had a trend to decrease. Sirius red staining showed a decrease in the PST3.1a treated group although it did not reach statistical significance (8.4% ± 1.7SNx versus 6.7% ± 0.2 SNx + PST3.1a). PHA-L and galectin 3 expressions were increased in SNx animals, and the overexpression was blunted in PST3.1a treated animals (9.4% ± 1.5 SNx versus 5.7% ± 0.2 SNx + PST3.1a; P < 0.05 for galectin 3) (Fig. 2). CONCLUSION Fibrosis was observed in SNx animals 4 weeks after surgery. PST3.1a significantly decreased MGAT5 activity. Treatment with PST3.1a decreased fibrosis and significantly downregulated col1 and col4. These data show that PST3.1a treatment through MGAT5 inhibition may be a new treatment for fibrosis in the context of CKD.