1. ADAMTS13 inhibits oxidative stress and ameliorates progressive chronic kidney disease following ischaemia/reperfusion injury.
- Author
-
Zhou S, Guo J, Zhao L, Liao Y, Zhou Q, Cui Y, Hu W, Chen J, Ren X, Wei Q, Jiang S, Zheng Y, Li L, Wilcox CS, Persson PB, Patzak A, Tian J, and Yin Lai E
- Subjects
- ADAMTS13 Protein, Animals, Humans, Mice, Mice, Inbred C57BL, Oxidative Stress, von Willebrand Factor metabolism, Acute Kidney Injury, Renal Insufficiency, Chronic drug therapy, Reperfusion Injury drug therapy
- Abstract
Aims: Reduced A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif member 13 (ADAMTS13) levels are observed in kidney disease. We test whether recombinant human ADAMTS13 (rhADAMTS13) mitigates renal injury in chronic kidney disease (CKD) and the potential mechanisms., Methods: CKD was established 3 months after ischaemia/reperfusion (IR). ADAMTS13 and von Willebrand factor (vWF) levels, renal function and morphological changes were analysed. Afferent arteriolar responses to angiotensin II (Ang II) and acetylcholine (ACh) were measured. Oxidative stress-related molecules were detected., Results: Higher vWF and lower ADAMTS13 levels were observed in CKD mice, which were markedly attenuated by rhADAMTS13. rhADAMTS13 alleviated renal dysfunction, as documented by decreased blood urea nitrogen (BUN), serum creatinine, kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) levels in CKD mice. Moreover, rhADAMTS13 attenuated transforming growth factor (TGF)-β1/Smad3 activation. Plasma vWF: ADAMTS13 ratio showed positive correlations with malondialdehyde (MDA), hydrogen peroxide (H
2 O2 ) and proteinuria, and correlated inversely with superoxide dismutase (SOD) and catalase (CAT). Finally, rhADAMTS13 inhibited reactive oxygen species (ROS) levels and improved microvascular functional disorders, accompanied by the inhibition of glycogen synthase kinase (GSK) 3β hyperactivity and upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression., Conclusions: Acute kidney injury (AKI) reduces the expression of ADAMTS13 that contributes to progressive CKD, microvascular dysfunction, oxidative stress, inhibition of Nrf2 activity and renal histopathological damage. All of which can be alleviated by administration of rhADAMTS13., (© 2020 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)- Published
- 2021
- Full Text
- View/download PDF