Endoglin regulates renal ischaemia–reperfusion injury

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Abstract

Background

Renal ischaemia–reperfusion (I–R) can cause acute tubular necrosis and chronic renal deterioration. Endoglin, an accessory receptor for Transforming Growth Factor-β1 (TGF-β1), 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.

Results

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-β1 and collagen IV (α1) 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.

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