Endoglin regulates renal ischaemia-reperfusion injury.

Abstract

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.

• Authors: Neil G Docherty, José M López-Novoa, Miguel Arevalo, Annette Düwel, Ana Rodriguez-Peña, Fernando Pérez-Barriocanal, Carmelo Bernabeu, Nélida Eleno
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 21 Issue 8 Pg. 2106-19 (Aug 2006) ISSN: 0931-0509 [Print] England
• PMID: 16751653 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Antigens, Differentiation, Myelomonocytic
• CD68 protein, mouse
• Collagen Type IV
• Endoglin
• Eng protein, mouse
• Eng protein, rat
• Intracellular Signaling Peptides and Proteins
• RNA, Messenger
• Transforming Growth Factor beta1
• Vascular Cell Adhesion Molecule-1
• Creatinine
• Peroxidase
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse

Topics

• Animals
• Antigens, CD (biosynthesis, genetics)
• Antigens, Differentiation, Myelomonocytic (biosynthesis, genetics)
• Collagen Type IV (biosynthesis, genetics)
• Creatinine (blood)
• Endoglin
• Endothelium, Vascular (metabolism, pathology)
• Enzyme Induction
• Fibrosis
• Gene Expression Regulation
• Heterozygote
• Inflammation
• Intracellular Signaling Peptides and Proteins (genetics, physiology)
• Kidney (blood supply, metabolism, pathology)
• Kidney Tubular Necrosis, Acute (etiology, physiopathology)
• Macrophages (enzymology, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Monocytes (enzymology, pathology)
• Nitric Oxide Synthase Type II (biosynthesis, genetics)
• Peroxidase (analysis)
• RNA, Messenger (biosynthesis)
• Rats
• Rats, Wistar
• Reperfusion Injury (complications, physiopathology)
• Transforming Growth Factor beta1 (biosynthesis, genetics)
• Vascular Cell Adhesion Molecule-1 (biosynthesis, genetics)