CD47 regulates renal tubular epithelial cell self-renewal and proliferation following renal ischemia reperfusion.
Defects in renal tubular epithelial cell repair contribute to renal ischemia reperfusion injury, cause acute kidney damage, and promote chronic renal disease. The matricellular protein thrombospondin-1 and its receptor CD47 are involved in experimental renal ischemia reperfusion injury, although the role of this interaction in renal recovery is unknown. We found upregulation of self-renewal genes (transcription factors Oct4, Sox2, Klf4 and cMyc) in the kidney of CD47(-/-) mice after ischemia reperfusion injury. Wild-type animals had minimal self-renewal gene expression, both before and after injury. Suggestive of cell autonomy, CD47(-/-) renal tubular epithelial cells were found to increase expression of the self-renewal genes. This correlated with enhanced proliferative capacity compared with cells from wild-type mice. Exogenous thrombospondin-1 inhibited self-renewal gene expression in renal tubular epithelial cells from wild-type but not CD47(-/-) mice, and this was associated with decreased proliferation. Treatment of renal tubular epithelial cells with a CD47 blocking antibody or CD47-targeting small interfering RNA increased expression of some self-renewal transcription factors and promoted cell proliferation. In a syngeneic kidney transplant model, treatment with a CD47 blocking antibody increased self-renewal transcription factor expression, decreased tissue damage, and improved renal function compared with that in control mice. Thus, thrombospondin-1 via CD47 inhibits renal tubular epithelial cell recovery after ischemia reperfusion injury through inhibition of proliferation/self-renewal.
Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Division of Renal and Electrolytes, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Natasha M
NM
Rogers
Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA.
Zheng J
ZJ
Zhang
Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA.
Jiao-Jing
JJ
Wang
Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Angus W
AW
Thomson
Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Electronic address: jsi5@pitt.edu.
Jeffrey S
JS
Isenberg
D000818:Animals; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000502:physiology*; D006801:Humans; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D000090062:Kruppel-Like Factor 4; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D061251:Primary Cell Culture; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012038:Regeneration; D015427:Reperfusion Injury / Q000150:complications*; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
D051928:CD47 Antigen; C497894:CD47 protein, human; C497895:Cd47 protein, mouse; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D034741:RNA, Small Interfering; D019700:Thrombospondin 1; D014157:Transcription Factors; C585483:Thbs1 protein, mouse
CD47; OSKM; ischemia-reperfusion injury; kidney; self-renewal; thrombospondin-1