Importantly, the study also confirmed the mechanism of action of two DPEP-1 inhibitors, the LSALT peptide (Metablok) and cilastatin that effectively protected the kidney during ischemia reperfusion injury. Both the LSALT peptide and cilastatin are protected by composition and method of use patents for AKI respectively and held by Arch Biopartners.
Arthur Lau, Jennifer J. Rahn, Mona Chappellaz, Hyunjae Chung, Hallgrimur Benediktsson, Dominique Bihan, Anne Von Mässenhausen, Andreas Linkermann, Craig N. Jenne, Stephen M. Robbins, Donna L. Senger, Ian A. Lewis, Justin Chun and Daniel A. Muruve
The mechanisms that drive leukocyte recruitment to the kidney are incompletely understood. Dipeptidase-1 (DPEP1) is a major neutrophil adhesion receptor highly expressed on proximal tubular cells and peritubular capillaries of the kidney. Renal ischemia reperfusion injury (IRI) induces robust neutrophil and monocyte recruitment and causes acute kidney injury (AKI). Renal inflammation and the AKI phenotype were attenuated in Dpep1−/− mice or mice pretreated with DPEP1 antagonists, including the LSALT peptide, a nonenzymatic DPEP1 inhibitor. DPEP1 deficiency or inhibition primarily blocked neutrophil adhesion to peritubular capillaries and reduced inflammatory monocyte recruitment to the kidney after IRI. CD44 but not ICAM-1 blockade also decreased neutrophil recruitment to the kidney during IRI and was additive to DPEP1 effects. DPEP1, CD44, and ICAM-1 all contributed to the recruitment of monocyte/macrophages to the kidney following IRI. These results identify DPEP1 as a major leukocyte adhesion receptor in the kidney and potential therapeutic target for AKI.