[ODP-163] Stx2 disturbs circadian rhythm in the proximal tubular epithelial cells in vitro and in vivo
Shiga toxin-producing Escherichia coli (STEC) causes proximal tubular defects in the kidney. Mouse kidney tissues after Stx2 injection were used for microarray analysis. Also, human primary renal proximal tubular epithelial cell (RPTEC) culture was treated with Stx2, and microarray was carried out. We compared murine kidney and RPTEC arrays and found 58 common differentially expressed genes (DEGs). We found that the most highly expressed gene was GDF15, which may be involved in Stx2-induced weight loss. Matricellular proteins CYR61 (CCN1) and CTGF (CCN2) may have reflected Stx2-induced src kinase Yes phosphorylation pathway activation, and later influenced by an earlier cell loss-associated wound repair mechanism. An increase in CHOP (DDIT3) indicated Stx2-induced ER-stress. We observed several ER-stress and ribotoxic stress response-associated DEGs. Moreover, circadian clock core gene PER1 and clock-controlled genes NR1D1, NFIL3 and CCRN4L were differentially expressed suggesting Stx2-induced renal circadian rhythm disturbance. Circadian rhythm-regulated proximal tubular Na+-glucose transporter SGLT1 (SLC5A1) was down-regulated, and mice developed glucosuria confirming proximal tubular dysfunction. We conclude that Stx2 alters gene expressions in murine and human proximal tubules and causes proximal tubular dysfunctions through circadian rhythm disturbance.