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Alpha-1-microglobulin protects from heme induced placenta and kidney damage in a pregnant ewe model for preeclampsia

Edström-Hägerwall, Anneli LU ; Hansson, Stefan LU orcid ; Casslén, Vera LU ; Rosenlöf, Lena ; Axelsson, Josefin LU ; Rippe, Bengt LU ; Marsal, Karel LU ; Mörgelin, Matthias LU ; Åkerström, Bo LU and Gram, Magnus LU orcid (2013) European Congress of the International Society for the Study of Hypertension in Pregnancy In Pregnancy Hypertension 3(2). p.1-70
Abstract

INTRODUCTION: Previous gene expression analysis have identified fetal hemoglobin (HbF) as a plausible etiological factor in preeclampsia. Free hemoglobin and its degradation products, e.g. heme, are known to cause oxidative stress, tissue damage, and vaso-constriction, typical findings in preeclampsia.

OBJECTIVE: To study alpha-1-microglobulin (A1M), an endogenous radical scavenger and heme-binder, as a potential treatment for preeclampsia using the pregnant ewe preeclampsia model. Free Hb and heme are known to take part in the pathology of this model and therefor well suited for evaluation of recombinant A1M as a therapy.

METHODS: 11 pregnant ewes, at gestational age 125-131 days, were acclimatized for 36h and then starved... (More)

INTRODUCTION: Previous gene expression analysis have identified fetal hemoglobin (HbF) as a plausible etiological factor in preeclampsia. Free hemoglobin and its degradation products, e.g. heme, are known to cause oxidative stress, tissue damage, and vaso-constriction, typical findings in preeclampsia.

OBJECTIVE: To study alpha-1-microglobulin (A1M), an endogenous radical scavenger and heme-binder, as a potential treatment for preeclampsia using the pregnant ewe preeclampsia model. Free Hb and heme are known to take part in the pathology of this model and therefor well suited for evaluation of recombinant A1M as a therapy.

METHODS: 11 pregnant ewes, at gestational age 125-131 days, were acclimatized for 36h and then starved for another 36h to induce preeclampsia symptoms. At the end of starvation period, they were treated either with placebo (n=6) or A1M injections (n=5). After injections, food was re-introduced and ewes further followed for 72h. The ewes were sacrificed the 6th day after beginning of acclimatization. Throughout the 6 days, the animals were monitored for blood pressure and different blood and urine parameters. Whole blood, kidney and placenta tissue samples were collected from the ewes. Gene expression analysis, blood analysis, histology and electron microscopy were used to evaluate the therapeutic effects of A1M.

RESULTS: Starvation increased the amount of free heme in the blood. The ultrastructure of the placenta and kidney were damaged in a way similar to what previously have been described for PE. The glomeruli and the tubuli were damaged which was reflected by increased Ficol clearance and increased plasma creatinine levels. Treatment with A1M significantly normalized the kidney functions. The most profound changes on gene expression level were found in white blood cells in the starved animals. Starvation decreases mRNA expression for anti-oxidants such as CAT (P=0.04), SOD1 (P=0.008), SOD2 (1.8-fold) as well as angiogenetic factors such as VEGF (P=0.02) and HGF (1.6-fold). A1M treatment rescued the decreased expression of SOD2 (P=0.04) and HGF (2-fold).

CONCLUSION: A1M is well tolerated and shows high potential as a treatment for PE-like symptoms in the pregnant ewe model for PE.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Journal Article
in
Pregnancy Hypertension
volume
3
issue
2
article number
PP010
pages
2 pages
publisher
Elsevier
conference name
European Congress of the International Society for the Study of Hypertension in Pregnancy
conference location
Tromsö, Norway
conference dates
2013-06-12 - 2013-06-14
external identifiers
  • pmid:26105866
ISSN
2210-7789
DOI
10.1016/j.preghy.2013.04.038
language
English
LU publication?
yes
id
8c77ae7d-31df-4964-8c5c-b02c0202af30
date added to LUP
2018-04-25 16:13:47
date last changed
2021-04-29 02:35:43
@misc{8c77ae7d-31df-4964-8c5c-b02c0202af30,
  abstract     = {{<p>INTRODUCTION: Previous gene expression analysis have identified fetal hemoglobin (HbF) as a plausible etiological factor in preeclampsia. Free hemoglobin and its degradation products, e.g. heme, are known to cause oxidative stress, tissue damage, and vaso-constriction, typical findings in preeclampsia.</p><p>OBJECTIVE: To study alpha-1-microglobulin (A1M), an endogenous radical scavenger and heme-binder, as a potential treatment for preeclampsia using the pregnant ewe preeclampsia model. Free Hb and heme are known to take part in the pathology of this model and therefor well suited for evaluation of recombinant A1M as a therapy.</p><p>METHODS: 11 pregnant ewes, at gestational age 125-131 days, were acclimatized for 36h and then starved for another 36h to induce preeclampsia symptoms. At the end of starvation period, they were treated either with placebo (n=6) or A1M injections (n=5). After injections, food was re-introduced and ewes further followed for 72h. The ewes were sacrificed the 6th day after beginning of acclimatization. Throughout the 6 days, the animals were monitored for blood pressure and different blood and urine parameters. Whole blood, kidney and placenta tissue samples were collected from the ewes. Gene expression analysis, blood analysis, histology and electron microscopy were used to evaluate the therapeutic effects of A1M.</p><p>RESULTS: Starvation increased the amount of free heme in the blood. The ultrastructure of the placenta and kidney were damaged in a way similar to what previously have been described for PE. The glomeruli and the tubuli were damaged which was reflected by increased Ficol clearance and increased plasma creatinine levels. Treatment with A1M significantly normalized the kidney functions. The most profound changes on gene expression level were found in white blood cells in the starved animals. Starvation decreases mRNA expression for anti-oxidants such as CAT (P=0.04), SOD1 (P=0.008), SOD2 (1.8-fold) as well as angiogenetic factors such as VEGF (P=0.02) and HGF (1.6-fold). A1M treatment rescued the decreased expression of SOD2 (P=0.04) and HGF (2-fold).</p><p>CONCLUSION: A1M is well tolerated and shows high potential as a treatment for PE-like symptoms in the pregnant ewe model for PE.</p>}},
  author       = {{Edström-Hägerwall, Anneli and Hansson, Stefan and Casslén, Vera and Rosenlöf, Lena and Axelsson, Josefin and Rippe, Bengt and Marsal, Karel and Mörgelin, Matthias and Åkerström, Bo and Gram, Magnus}},
  issn         = {{2210-7789}},
  keywords     = {{Journal Article}},
  language     = {{eng}},
  note         = {{Conference Abstract}},
  number       = {{2}},
  pages        = {{1--70}},
  publisher    = {{Elsevier}},
  series       = {{Pregnancy Hypertension}},
  title        = {{Alpha-1-microglobulin protects from heme induced placenta and kidney damage in a pregnant ewe model for preeclampsia}},
  url          = {{http://dx.doi.org/10.1016/j.preghy.2013.04.038}},
  doi          = {{10.1016/j.preghy.2013.04.038}},
  volume       = {{3}},
  year         = {{2013}},
}