Trehalose Alleviates Nephropathy in Focal Segmental Glomerulosclerosis via the Upregulation of WT-1/EZH2 Pathway

Maha Al-Asmakh^1,2Marwa Al Riyami³Miytha Al Marbuii⁴Shadia Al Sinawi³Suaad Said AL Badi³Faisal AL Ismaili⁵Amira Alkharusi⁶Razan Al Zadjali⁴Zaina Alharthi^4,7Sara Al Mashrafi⁴Razan Al Breiki⁴Sulaiman Al-Hashmi⁸Ali Al Lawati⁹Amal Kassab¹⁰FAHAD ZADJALI^11,4*

• ¹Department of Biomedical Sciences, College of Health Sciences, QU-Health, Qatar University, Doha, Qatar
• ²Biomedical Research Center, Qatar University, Doha, Qatar
• ³Department of Pathology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
• ⁴Department of Clinical Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
• ⁵Department of Medicine, The Royal Hospital, Muscat, Oman
• ⁶Department of Clinical Physiology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
• ⁷Ibra Branch, Oman College of Health Sciences, Ibra, Oman
• ⁸Laboratory for Stem Cell and Regenerative Medicine, Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
• ⁹Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman
• ¹⁰Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, 3775 University Street,, Montreal, Canada
• ¹¹Oman College of Health Sciences, Muscat, Oman

Focal segmental glomerulosclerosis (FSGS) is a serious disease that culminates in kidney failure. Today, FSGS is diagnosed histologically as a progressive scarring of the glomeruli due to gradual loss or damage of the podocyte layer, making it one of the main targets of FSGS therapeutic approaches. However, given that podocytes are terminally differentiated, post mitotic epithelial cells with limited proliferative capacity, they are considered one of the most vulnerable components of the glomeruli. We herein investigated the effect of trehalose, a naturally occurring sugar with low toxicity and high stability, on kidney function using a murine model of adriamycin-induced nephropathy. Based on our data, trehalose administration improved proteinuria in mice with FSGS compared to those without FSGS induction (24 hour urine protein of 0.30±0.06 versus 0.55±0.08, p-value<0.05, and urine protein to creatinine ratio of 0.78±0.25 versus 1.56±0.17, p-value<0.05, respectively this is accompanied by reduced fibrosis and podocyte damage. Significant reduction in collagen deposition in glomeruli observed in mice treated with trehalose , P-value<0.01 and significant reduction in glomerular basement membrane thickness, P-value<0.001. Moreover, trehalose intake is associated with higher mature podocyte markers at gene and protein expression levels, Nphs1, Nphs2 and Synpo. These favorable effects seem to be mediated mainly via increased WT-1/EZH2 signaling, which is a key pathway in maintaining normal podocyte function and growth. These effects were also observed in the downstream signaling pathway with lower expression of Mmp-7 and Catenin 1 gene expression (p-value<0.05 and <0.01, respectively). Our findings suggest that trehalose could be a promising therapeutic agent for FSGS, nevertheless, more studies are necessary to confirm our findings and evaluate trehalose efficacy in clinical settings.