title: Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia.
abstract: Thrombospondin 1 (TSP-1) is a matricellular protein that inhibits angiogenesis and causes apoptosis in vivo and in vitro in several cancerous cells and tissues. Here we identify TSP-1 as the molecule with the highest induction level at 3 hours of IR injury in rat and mouse kidneys subjected to ischemia/reperfusion (IR) injury using the DNA microarray approach. Northern hybridizations demonstrated that TSP-1 expression was undetectable at baseline, induced at 3 and 12 hours, and returned to baseline levels at 48 hours of reperfusion. Immunocytochemical staining identified the injured proximal tubules as the predominant sites of expression of TSP-1 in IR injury and showed colocalization of TSP-1 with activated caspase-3. Addition of purified TSP-1 to normal kidney proximal tubule cells or cells subjected to ATP depletion in vitro induced injury as demonstrated by cytochrome c immunocytochemical staining and caspase-3 activity. The deleterious role of TSP-1 in ischemic kidney injury was demonstrated directly in TSP-1 null mice, which showed significant protection against IR injury-induced renal failure and tubular damage. We propose that TSP-1 is a novel regulator of ischemic damage in the kidney and may play an important role in the pathophysiology of ischemic kidney failure.
authors.affiliation: Department of Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio 45267-0585, USA.
authors.forename: Charuhas V
authors.initials: CV
authors.lastname: Thakar
authors.forename: Kamyar
authors.initials: K
authors.lastname: Zahedi
authors.forename: Monica P
authors.initials: MP
authors.lastname: Revelo
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Wang
authors.forename: Charles E
authors.initials: CE
authors.lastname: Burnham
authors.forename: Sharon
authors.initials: S
authors.lastname: Barone
authors.forename: Shannon
authors.initials: S
authors.lastname: Bevans
authors.forename: Alex B
authors.initials: AB
authors.lastname: Lentsch
authors.forename: Hamid
authors.initials: H
authors.lastname: Rabb
authors.forename: Manoocher
authors.initials: M
authors.lastname: Soleimani
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D015152:Blotting, Northern; D015153:Blotting, Western; D018955:CD36 Antigens / Q000096:biosynthesis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003124:Colorimetry; D045304:Cytochromes c / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004789:Enzyme Activation; D017353:Gene Deletion; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007511:Ischemia / Q000473:pathology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019700:Thrombospondin 1 / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
chemical_list: D018955:CD36 Antigens; D018076:DNA, Complementary; D012333:RNA, Messenger; D019700:Thrombospondin 1; D012313:RNA; D000255:Adenosine Triphosphate; D045304:Cytochromes c; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases