Zablocki, A.; Marques, E.; Yammine, L.; Nguyen, C.; Terzi, F.; Gallazzini, M.

Background: Lipocalin 2 (Lcn2), a small-secreted protein, is an established sensitive biomarker of kidney injury. In Cisplatin (CDDP) induced acute kidney injury (AKI), Lcn2 expression is swiftly and strongly increased in suffering renal medullary tubules. While recent reports correlates Lcn2 expression in cancer cells with CDDP resistance, the role of Lcn2 in kidney tubule damaged by CDDP remains unknown. Methods: To better understand the role of Lcn2 in CDDP-induced AKI, experiments on Lcn2+/+ or Lcn2-/- mice as well as immortalized kidney cells knock-down (KD) for Lcn2 were conducted. Kidney function and injury were assessed using standard techniques. Cellular and molecular mechanisms were studied in WT and Lcn2 KD cells in combination with pathways inhibitors in order to gain insight Lcn2 driven mechanisms. Results: In animal injected with CDDP, Lcn2 was upregulated mostly in kidney inner medulla collecting duct while it was reabsorbed in the proximal tubules. Lcn2-/- in mice significantly decreased kidney function compare to WT mice, while it increased parenchymal damage due to increased cell death and cast formation. Interestingly, while little to no damage were present in the medulla of CDDP injected WT animal, a clear increase of medulla tubular lesions was observed in Lcn2-/- mice. Using Inner Medullary Collecting Duct cells (mIMDC-3), we showed that Lcn2 KD induces a p53-dependent apoptosis upon Cisplatin exposure while no effect on necrosis was observed. Finally, we demonstrated that Lcn2 drives CDDP resistance to apoptosis through the activation of the pro-survival EGFR pathway. Conclusions: We established that Lcn2 is a renoprotective protein in CDDP-induced AKI via the activation of EGFR pathway. This new mechanism might represent a new approach for the treatment of AKI. Keywords: acute kidney injury, cisplatin, Lipocalin-2, apoptosis, EGFR.