rhADAMTS13 reduces oxidative stress by cleaving VWF in ischaemia/reperfusion‐induced acute kidney injury

Abstract

Aims: Acute kidney injury (AKI), a major health burden, lacks effective therapy.Anti-inflammatory actions of a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 (ADAMTS13) may provide a new treatment option for AKI. Along with inflammation, oxidative stress is critical for AKI development, yet the impact of ADAMTS13 on oxidative stress in AKI remains to be fully elucidated. Methods:We assess recombinant human ADAMTS13 (rhADAMTS13) actions on oxidative stress in a murine ischaemia/reperfusion (IR) model. Antioxidant stress-enzyme activities, renal morphology, kidney function markers and vascular function of isolated afferent arterioles are quantified.Results: rhADAMTS13 provided after IR, reduces blood urea nitrogen (BUN) by 33% and serum creatinine (Scr) by 73% in 24 hours post-IR. rhADAMTS13 reduces BUN (40.03 ± 20.34 mmol/L vs 72.35 ± 18.74 mmol/L, P < .01), Scr (75.67 ± 51.19 μmol/L vs 176.17 ± 55.38 μmol/L, P < .01) and proteinuria by 41% in 48 hours post-IR as well. Moreover, rhADAMTS13 administration decreases malondialdehyde (MDA) and increases the activity of antioxidant stress enzymes, and attenuates reactive oxygen species production. rhADAMTS13 also upregulates nuclear factor-erythroid-2-related factor 2/haem oxygenase-1, enhances antioxidant enzymes activity and alleviates endothelial dysfunction. Finally,

Cathepsin K deficiency prevented stress-related thrombosis in a mouse FeCl3 model

“…Our in vitro CTSK genetic modification yielded the same results in HUVECs. Oxidative stress has been shown to produce a prothrombotic state via the regulation of ADAMTS13 and vWF expressions and/or modifications [ 52 ]. These findings thus suggest that both genetic and pharmacological treatments might rectify the changes in arterial oxidative stress, resulting in a vasculoprotective effect on endothelial damage/apoptosis and the imbalance of endothelial cell-derived vWF and ADAMTS13, thereby preventing thrombosis in mice subjected to our stress conditions.…”

Current insights into the Pathophysiology of kidney diseases

“…This may lead to the increasing antioxidant capacity of ADAMTS13 in ischemic kidneys and identifies rADAMTS13 as a potential future therapeutic option for the broad treatment of AKI. 5 If AKI has developed, the GFR is increased in order to maintain kidney function. 6 Up to a loss of 50% of the functional nephrons, full GFR can still be ensured, which is also often the reason for the late diagnosis of AKI.…”

“…On the molecular level ADAMTS13 caused the upregulation of nuclear factor‐erythroid 2‐related factor2 (Nrf2) and thereby upregulated the expression of, for example, heme oxygenase‐1 (HO‐1), a key cytoprotective enzyme. This may lead to the increasing antioxidant capacity of ADAMTS13 in ischemic kidneys and identifies rADAMTS13 as a potential future therapeutic option for the broad treatment of AKI 5 …”

Prolyl hydroxylase inhibitors, polydrug use, and the phosphoproteome

“…Development of treatment strategies for kidney diseases largely relies on experimental models of ureteral obstruction/tubular-interstitial fibrosis, 1,2 acute kidney injury/ ischemia/reperfusion, 3,4 cyclosporine toxicity 5,6 or diabetic nephropathy. 7 However, experimental models only partly replicate the respective human disease.…”