rA1M-035, a Physicochemically Improved Human Recombinant α1 -Microglobulin, Has Therapeutic Effects in Rhabdomyolysis-Induced Acute Kidney Injury

Antioxidants & Redox Signaling
Bo ÅkerströmMagnus Gram

Abstract

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. 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...Continue Reading

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Citations

Oct 4, 2020·International Journal of Molecular Sciences·Amanda KristianssonJill R Storry
May 11, 2019·BMC Pregnancy and Childbirth·Sophia GrimesDaniel J Corsi
Aug 23, 2020·International Journal of Molecular Sciences·Amanda KristianssonMagnus Gram
Jan 10, 2020·Annual Review of Pharmacology and Toxicology·Michaela Gebauer, Arne Skerra
Mar 23, 2021·Frontiers in Physiology·Jesper BergwikBo Åkerström
Nov 11, 2021·Experimental Hematology·Sara E SjögrenJohan Flygare

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Methods Mentioned

BETA
glycosylation
size
dynamic
electrophoresis
size-exclusion chromatography
surface plasmon resonance
ABTS
ion-exchange chromatography
chips
FCS

Software Mentioned

iCycler iQ Optical System
Image Lab
Image Lab [UNK]

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