Endoglin regulates renal ischaemia-reperfusion injury.
BACKGROUND
Renal ischaemia-reperfusion (I-R) can cause acute tubular necrosis and chronic renal deterioration. Endoglin, an accessory receptor for Transforming Growth Factor-beta1 (TGF-beta1), is expressed on activated endothelium during macrophage maturation and implicated in the control of fibrosis, angiogenesis and inflammation.


METHODS
Endoglin expression was monitored over 14 days after renal I-R in rats. As endoglin-null mice are not viable, the role of endoglin in I-R was studied by comparing renal I-R injury in haploinsufficient mice (Eng(+/-)) and their wild-type littermates (Eng(+/+)). Renal function, morphology and molecular markers of acute renal injury and inflammation were compared.


RESULTS
Endoglin mRNA up-regulation in the post-ischaemic kidneys of rats occurred at 12 h after I-R; endoglin protein levels were elevated throughout the study period. Expression was initially localized to the vascular endothelium, then extended to fibrotic and inflamed areas of the interstitium. Two days after I-R, plasma creatinine elevation and acute tubular necrosis were less marked in Eng(+/-) than in Eng(+/+) mice. Significant up-regulation of endoglin protein was found only in the post-ischaemic kidneys of Eng(+/+) mice and coincided with an increased mRNA expression of the TGF-beta1 and collagen IV (alpha1) chain genes. Significant increases in vascular cell adhesion molecule-1 (VCAM-1) and inducible nitric oxide synthase (iNOS) expression, nitrosative stress, myeloperoxidase activity and CD68 staining for macrophages were evident in post-ischaemic kidneys of Eng(+/+), but not Eng(+/-) mice, suggesting that impaired endothelial activation and macrophage maturation may account for the reduced injury in post-ischaemic kidneys of Eng(+/-) mice.


CONCLUSIONS
Endoglin is up-regulated in the post-ischaemic kidney and endoglin-haploinsufficient mice are protected from renal I-R injury. Endoglin may play a primary role in promoting inflammatory responses following renal I-R.
Docherty
Neil G
NG
Departamento de Fisiología y Farmacología, Edificio Departamental, Campus Miguel de Unamuno 37007, Salamanca, Spain.
López-Novoa
José M
JM
Arevalo
Miguel
M
Düwel
Annette
A
Rodriguez-Peña
Ana
A
Pérez-Barriocanal
Fernando
F
Bernabeu
Carmelo
C
Eleno
Nélida
N
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis / Q000235:genetics; D024141:Collagen Type IV / Q000096:biosynthesis / Q000235:genetics; D003404:Creatinine / Q000097:blood; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D004790:Enzyme Induction; D005355:Fibrosis; D005786:Gene Expression Regulation; D006579:Heterozygote; D007249:Inflammation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D007683:Kidney Tubular Necrosis, Acute / Q000209:etiology / Q000503:physiopathology*; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000201:enzymology / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D009195:Peroxidase / Q000032:analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000150:complications / Q000503:physiopathology*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D024141:Collagen Type IV; D003404:Creatinine; D000071063:Endoglin; D047908:Intracellular Signaling Peptides and Proteins; D052247:Nitric Oxide Synthase Type II; D009195:Peroxidase; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D019010:Vascular Cell Adhesion Molecule-1; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C502004:Eng protein, mouse; C501740:Eng protein, rat; C496317:Nos2 protein, mouse