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rA1M-035, a Physicochemically Improved Human Recombinant α-Microglobulin, Has Therapeutic Effects in Rhabdomyolysis-Induced Acute Kidney Injury

Åkerström, Bo LU ; Rosenlöf, Lena; Hägerwall, Anneli; Rutardottir, Sigurbjörg LU ; Ahlstedt, Jonas LU ; Johansson, Maria E LU ; Erlandsson, Lena LU ; Allhorn, Maria LU and Gram, Magnus LU (2019) In Antioxidants and Redox Signaling 30(4). p.489-504
Abstract

AIMS: Human α1-microglobulin (A1M) is an endogenous reductase and radical- and heme-binding protein with physiological antioxidant protective functions. Recombinant human A1M (rA1M) has been shown to have therapeutic properties in animal models of preeclampsia, a pregnancy disease associated with oxidative stress. Recombinant A1M, however, lacks glycosylation, and shows lower solubility and stability than A1M purified from human plasma. The aims of this work were to (i) use site-directed mutagenesis to improve the physicochemical properties of rA1M, (ii) demonstrate that the physicochemically improved rA1M displays full in vitro cell protective effects as recombinant wild-type A1M (rA1M-wt), and (iii) show its therapeutic potential in... (More)

AIMS: Human α1-microglobulin (A1M) is an endogenous reductase and radical- and heme-binding protein with physiological antioxidant protective functions. Recombinant human A1M (rA1M) has been shown to have therapeutic properties in animal models of preeclampsia, a pregnancy disease associated with oxidative stress. Recombinant A1M, however, lacks glycosylation, and shows lower solubility and stability than A1M purified from human plasma. The aims of this work were to (i) use site-directed mutagenesis to improve the physicochemical properties of rA1M, (ii) demonstrate that the physicochemically improved rA1M displays full in vitro cell protective effects as recombinant wild-type A1M (rA1M-wt), and (iii) show its therapeutic potential in vivo against acute kidney injury (AKI), another disease associated with oxidative stress.

RESULTS: A novel recombinant A1M-variant (rA1M-035) with three amino acid substitutions was constructed, successfully expressed, and purified. rA1M-035 had improved solubility and stability compared with rA1M-wt, and showed intact in vitro heme-binding, reductase, antioxidation, and cell protective activities. Both rA1M-035 and rA1M-wt showed, for the first time, potential in vivo protective effects on kidneys using a mouse rhabdomyolysis glycerol injection model of AKI.

INNOVATION: A novel recombinant A1M-variant, rA1M-035, was engineered. This protein showed improved solubility and stability compared with rA1M-wt, full in vitro functional activity, and potential protection against AKI in an in vivo rhabdomyolysis mouse model.

CONCLUSION: The new rA1M-035 is a better drug candidate than rA1M-wt for treatment of AKI and preeclampsia in human patients. Antioxid. Redox Signal. 00, 000-000.

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author
organization
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subject
keywords
Journal Article
in
Antioxidants and Redox Signaling
volume
30
issue
4
pages
489 - 504
publisher
Mary Ann Liebert, Inc.
ISSN
1557-7716
DOI
10.1089/ars.2017.7181
language
English
LU publication?
yes
id
33596cd8-161c-48f1-9df7-c923e6f57b0a
date added to LUP
2018-04-25 16:12:47
date last changed
2019-02-01 04:30:01
@article{33596cd8-161c-48f1-9df7-c923e6f57b0a,
  abstract     = {<p>AIMS: Human α1-microglobulin (A1M) is an endogenous reductase and radical- and heme-binding protein with physiological antioxidant protective functions. Recombinant human A1M (rA1M) has been shown to have therapeutic properties in animal models of preeclampsia, a pregnancy disease associated with oxidative stress. Recombinant A1M, however, lacks glycosylation, and shows lower solubility and stability than A1M purified from human plasma. The aims of this work were to (i) use site-directed mutagenesis to improve the physicochemical properties of rA1M, (ii) demonstrate that the physicochemically improved rA1M displays full in vitro cell protective effects as recombinant wild-type A1M (rA1M-wt), and (iii) show its therapeutic potential in vivo against acute kidney injury (AKI), another disease associated with oxidative stress.</p><p>RESULTS: A novel recombinant A1M-variant (rA1M-035) with three amino acid substitutions was constructed, successfully expressed, and purified. rA1M-035 had improved solubility and stability compared with rA1M-wt, and showed intact in vitro heme-binding, reductase, antioxidation, and cell protective activities. Both rA1M-035 and rA1M-wt showed, for the first time, potential in vivo protective effects on kidneys using a mouse rhabdomyolysis glycerol injection model of AKI.</p><p>INNOVATION: A novel recombinant A1M-variant, rA1M-035, was engineered. This protein showed improved solubility and stability compared with rA1M-wt, full in vitro functional activity, and potential protection against AKI in an in vivo rhabdomyolysis mouse model.</p><p>CONCLUSION: The new rA1M-035 is a better drug candidate than rA1M-wt for treatment of AKI and preeclampsia in human patients. Antioxid. Redox Signal. 00, 000-000.</p>},
  author       = {Åkerström, Bo and Rosenlöf, Lena and Hägerwall, Anneli and Rutardottir, Sigurbjörg and Ahlstedt, Jonas and Johansson, Maria E and Erlandsson, Lena and Allhorn, Maria and Gram, Magnus},
  issn         = {1557-7716},
  keyword      = {Journal Article},
  language     = {eng},
  number       = {4},
  pages        = {489--504},
  publisher    = {Mary Ann Liebert, Inc.},
  series       = {Antioxidants and Redox Signaling},
  title        = {rA1M-035, a Physicochemically Improved Human Recombinant α-Microglobulin, Has Therapeutic Effects in Rhabdomyolysis-Induced Acute Kidney Injury},
  url          = {http://dx.doi.org/10.1089/ars.2017.7181},
  volume       = {30},
  year         = {2019},
}