M EL-RASHID1,2, B SANGANERIA1, N ROGERS1,2,3
1Westmead Institute for Medical Research, Westmead, Australia, 2The University of Sydney, Camperdown, Australia, 3Westmead Hospital, Westmead, Australia
Aim: To explore the role of CD47 in acute kidney injury and its therapeutic potential.
Background: Acute kidney injury (AKI) initiates a complex pathophysiological cascade leading to epithelial cell death. Recent studies identify autophagy, the mechanism of intracellular degradation of cytoplasmic constituents, as important in protection against injury. We have reported that the protein thrombospondin-1 (TSP1), and its receptor CD47, are induced in AKI, however their role in regulating renal injury is unknown.
Methods: Age and gender-matched wild-type (WT) and CD47-/- mice were challenged with renal ischemia reperfusion injury. All animals underwent analysis of renal function and biomolecular phenotyping. Human and murine WT and CD47-/- renal tubular epithelial cells (rTEC) were studied in vitro.
Results: CD47-/- mice were resistant to AKI, with decreased serum creatinine (140±26 versus 59±15μmol/L, p<0.001), and ameliorated histological changes compared to WT animals. CD47-/- mice demonstrated concurrent upregulation of key autophagy genes, including Atg5, Atg7, Beclin-1, and LC3 at baseline and post-AKI. Electron microscopic examination of kidneys revealed increased autophagosome and autolysosome numbers in CD47-/- animals. WT mice demonstrated negligible autophagy expression at all time points. rTEC from CD47-/- mice displayed basal upregulation of autophagy that was preserved under hypoxic stress and correlated with enhanced viability when compared to WT cells. Treatment of WT rTEC with a CD47 oligonucleotide to block CD47 signalling increased autophagy. Finally, in a syngeneic mouse kidney transplantation model, treatment with a CD47 blocking antibody improved renal function, decreased histologic damage and increased autophagy compared to control mice.
Conclusions: These data suggest activated CD47 is a proximate promoter of AKI through inhibition of autophagy and point to CD47 as a target to restore renal function following injury.