Heterodimer of Erythropoietin Receptor and β Common Receptor in Renal Ischemia-­Reperfusion Injury and Repair

Acute kidney injury (AKI) is a common life-­threaten disease without specific treatment. Tissue protective receptor, erythropoietin receptor/β common receptor (EPOR/βcR), mediates the migration of injury to adaptive repair in ischaemia/reperfusion (IR)-­induced AKI. This project further studied the dynamic expression, role and mechanism of EPOR/βcR, its association with complement properdin, in murine IR kidneys and tubular epithelial cells (TECs). The potential of EPOR/βcR guided cell/organ target caspase-­3 (executing apoptosis and inflammation) siRNA delivery was also explored. A time course model of renal IR from 6 h to 1 w uncovered the gradual increase of EPOR/βcR in kidneys, localized mainly in TECs, providing an evidence of EPOR/βcR highly expressed in damaged TECs at the early stage of injury. At 72 h post IR, EPOR/βcR expression was increased greater in properdin deficient (PKO) mouse kidneys with aggravated damage, in which properdin might act as a pattern recognition molecule facilitating phagocytosis and clearing damaged cells. HBSP, a ligand of EPOR/βcR, preserved renal function andstructure in wild type and PKO mice, and further reduced interstitial apoptosis in PKO IR kidneys. PKO further elevated EPOR/βcR enhanced the renoprotection of HBSP by complementing deficient phagocytosis, reducing apoptosis and inflammation and promoting repair. Isolated TECs from wild type and PKO mice provided additional evidence that properdin released from TECs, but not serum, affected apoptosis and phagocytosis. In the 2-­w renal IR model, HBSP and caspase-­3 siRNA administered at the onset of injury synergistically decreased injury mediators and preserved kidney structure. In addition, fluorescein iridium labeled HBSP was reveled on TECs, and the apical surface of tubules predominately in IR kidneys. EPOR/βcR, therefore, associated with properdin, phagocytosis, apoptosis and inflammation, limits injury and promotes repair. Cell/organ target siRNA delivery might be achieved by siRNA conjugated HBSP guiding by highly expressed EPOR/βcR in injured cells of the organ.