Kidney Week

Abstract: TH-OR012

Activated CD47 Promotes AKI by Limiting Autophagy

Session Information

• Cellular Responses to Kidney Injury
  November 02, 2017 | Location: Room 395, Morial Convention Center
  Abstract Time: 04:42 PM - 04:54 PM

Category: Acute Kidney Injury

• 001 AKI: Basic

Authors

• Rogers, Natasha M., Westmead Institute for Medical Research, Sydney, New South Wales, Australia

Natasha M. Rogers, MD, PhD, FASN

• Sanganeria, Barkha, Westmead Institute for Medical Research, Sydney, New South Wales, Australia

Barkha Sanganeria,

• El-Rashid, Maryam, Westmead Institute for Medical Research, Sydney, New South Wales, Australia

Maryam El-Rashid,

Background

Renal ischemia reperfusion injury (IRI) initiates a complex pathophysiological cascade leading to epithelial cell death manifesting as acute kidney injury. 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 renal IRI, however the mechanism underlying the regulation of renal injury is unknown.

Methods

Age and gender-matched wild-type (WT) and CD47^-/- mice were challenged with bilateral renal IRI. 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 renal IRI at multiple time-points following reperfusion (24 h, 72 h, 168 h), with significantly decreased urea and creatinine (2.1±0.5 vs 0.9±0.3 mg/dl at 24 h, 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 at all reperfusion time-points. WT mice consistently demonstrated negligible autophagy expression in the kidney. However, p62 expression was not significantly different between WT and CD47^-/- mice. rTEC from CD47^-/- mice displayed basal upregulation of autophagy genes that was preserved under exogenous stress (hypoxia, FiO₂ 1%, or treatment with TSP1, 2.2nM for 24 h), and this correlated with enhanced viability when compared to WT cells. Treatment of WT rTEC with an oligonucleotide to block TSP1-CD47 signalling increased autophagy. Human rTEC similarly demonstrated downregulated autophagy in response to exogenous TSP1, which was mitigated in conjunction with a CD47-blocking antibody. Finally, in a syngeneic mouse kidney transplantation model, treatment with a CD47-blocking antibody improved renal function and decreased histologic damage compared to control mice, and this was associated with increased autophagy.

Conclusion

These data suggest activated CD47 is a proximate promoter of renal IRI through inhibition of autophagy and cell viability, and point to CD47 as a target to restore renal function following injury.

Funding

• Government Support - Non-U.S.