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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Standard

rA1M-035, a Physicochemically Improved Human Recombinant α-Microglobulin, Has Therapeutic Effects in Rhabdomyolysis-Induced Acute Kidney Injury. / Åkerström, Bo; Rosenlöf, Lena; Hägerwall, Anneli; Rutardottir, Sigurbjörg; Ahlstedt, Jonas; Johansson, Maria E; Erlandsson, Lena; Allhorn, Maria; Gram, Magnus.

I: Antioxidants and Redox Signaling, Vol. 30, Nr. 4, 02.2019, s. 489-504.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

APA

CBE

MLA

Vancouver

Author

RIS

TY - JOUR

T1 - rA1M-035, a Physicochemically Improved Human Recombinant α-Microglobulin, Has Therapeutic Effects in Rhabdomyolysis-Induced Acute Kidney Injury

AU - Åkerström, Bo

AU - Rosenlöf, Lena

AU - Hägerwall, Anneli

AU - Rutardottir, Sigurbjörg

AU - Ahlstedt, Jonas

AU - Johansson, Maria E

AU - Erlandsson, Lena

AU - Allhorn, Maria

AU - Gram, Magnus

PY - 2019/2

Y1 - 2019/2

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1089/ars.2017.7181

DO - 10.1089/ars.2017.7181

M3 - Article

VL - 30

SP - 489

EP - 504

JO - Antioxidants and Redox Signaling

T2 - Antioxidants and Redox Signaling

JF - Antioxidants and Redox Signaling

SN - 1557-7716

IS - 4

ER -