NIV Congres

Ischemia/reperfusion (I/R) injury is a key event in kidney transplantation. Recently, we demonstrated a crucial role for Mannan-binding lectin (MBL) in the pathogenesis of renal I/R injury. Ischemia is an important factor leading to impaired protein folding and consequent endoplasmic reticulum (ER) stress. GRP78/BIP, a stress-inducible ER chaperone, serves as a master modulator for the ER-stress response. In the present study we explored the role of MBL in the GRP78-induced ER-stress response.

Exposure of human tubular epithelial cells (TEC) to MBL in vitro resulted in binding and internalization of MBL. Confocal microscopy revealed strong colocalization with ER-stress sensor GRP78. Within two hours of MBL exposure, assessment of ER-stress markers sXBP-1 and CHOP, revealed atwenty- and tenfold induction respectively, which was accompanied by a strong IL-6 protein expression, another hallmark of ER-stress.

Assessment of rat sXBP-1 following I/R in vivo revealed an extensive induction of ER-stress within 2 hours, which was accompanied by an elevated expression of IL-6 and intra-epithelial presence of MBL. Interestingly, staining for GRP78 revealed a complete loss of protein expression in the cortico-medullary region already 2 hours after reperfusion, which was followed by loss of TEC adhesion and cell death within 24 hours. Importantly, inhibition of MBL completely prevented degradation of GRP78 in the cortico-medullary region, diminished the early IL-6 expression and protected against TEC injury.

In conclusion, inhibition of MBL prevents degradation of GRP78 and reduces IL-6 expression. Loss of GRP78 could be a possible mechanism by which MBL induces tubular epithelial injury following reperfusion.