ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: TH-OR016

CD47 Blockade Modulates Fibrosis in Chronic Kidney Injury

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Rogers, Natasha M., Westmead Institute for Medical Research, Westmead, New South Wales, Australia
  • Sanganeria, Barkha, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
Background

Acute kidney injury triggers a complex cascade of cellular esponses that can culminate in maladaptive repair and fibrosis. The matrix protein thrombospondin-1 (TSP1) is known to activate latent TGF-beta, a crucial mediator of fibrosis. We have previously reported that the TSP1 and its receptor CD47 are are induced following kidney injury. However, the role of this axis has not been characterized in chronic kidney disease.

Methods

Age and gender-matched wild-type (WT), CD47-/- and WT mice treated with CD47 blocking antibody (WT+αCD47Ab) were compared in two chronic kidney injury models: ischemia-reperfusion injury and contralateral nephrectomy (RN), and unilateral ureteric obstruction (UUO). 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

WT, WT + CD47Ab, and CD47-/- RN mice showed no difference in serum creatinine at 4 weeks regardless of injury model, however there was clear amelioration of renal histological changes and fibrosis with blockade or global knockout of CD47, defined by light microscopy and Sirius red staining. WT RN mice showed upregulated mRNA and protein expression of TSP-1 and pro-fibrotic markers TGF-ß, SMAD2, α-smooth muscle actin (SMA), fibronectin and type I collagen. These markers were significantly abrogated in both CD47-/- and WT + αCD47Ab counterparts. Interestingly, both WT and CD47-/- UUO mice at day+7 showed equivalent increases in pro-fibrotic tendency, by histology and qPCR, regardless of overall TSP1 expression. Only treatment with αCD47Ab reduced markers of matrix protein deposition. Renal tubular epithelial cells isolated from WT mice showed robust upregulation of TSP1 and elaborated pro-fibrotic markers under hypoxic stress, which was mitigated in CD47-/- cells. Incubation of rTEC with exogenous TSP1 demonstrated epithelia-to-mesenchyme transition with increased expression of TGF-ß and α-SMA. Immunohistochemistry of human kidney biopsy samples showed upregulated tubular TSP1 expression in stages 3-4 CKD (eGFR 15-59ml/min), and concurrently raised plasma TSP1 levels (8-10 fold) when compared to control samples (eGFR>60ml/min).

Conclusion

These data suggest that renal tubular epithelial cells contribute to fibrosis by activating TSP1-CD47 signalling, and point to CD47 as a target to limit fibrosis following some types of renal injury.

Funding

  • Government Support - Non-U.S.