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α1-microglobulin – Therapeutic opportunities in kidney and erythrocyte pathology

Kristiansson, Amanda LU (2021) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Oxidative stress is defined as an imbalance between oxidants and antioxidants. The reasons behind the condition are diverse, and can result in, or contribute to, the severity of many diseases. The body has different protective mechanisms to reduce the oxidative burden, among them a protein called α1-microglobulin (A1M). A1M possesses a unique set of molecular properties enabling it to act as a
radical scavenger, reductase and heme-binder. Most tissues express AMBP, the gene encoding A1M, but the liver is the main site of synthesis. A1M circulates in the blood and is catabolized in the kidneys.Therefore, two interesting sites of action for A1M are the blood and the kidneys.

The aim of this thesis was to investigate... (More)
Oxidative stress is defined as an imbalance between oxidants and antioxidants. The reasons behind the condition are diverse, and can result in, or contribute to, the severity of many diseases. The body has different protective mechanisms to reduce the oxidative burden, among them a protein called α1-microglobulin (A1M). A1M possesses a unique set of molecular properties enabling it to act as a
radical scavenger, reductase and heme-binder. Most tissues express AMBP, the gene encoding A1M, but the liver is the main site of synthesis. A1M circulates in the blood and is catabolized in the kidneys.Therefore, two interesting sites of action for A1M are the blood and the kidneys.

The aim of this thesis was to investigate new therapeutic opportunities for A1M, with focus on renal and erythrocyte pathology. Paper I studied in vitro heme-induced stress in human proximal tubule
epithelial cells. A1M prevented cell death, stress response and mitochondrial dysfunction. In paper II, a 177Lu-DOTATATE cancer treatment mouse model showed that the radiation induced DNA breaks as well as functional and histological damage to the kidneys. The A1M-treated mice, however, showed
significantly milder damage suggesting that A1M can be used as a radioprotector. Paper III investigated a 177Lu-PSMA-617 prostate cancer treatment mouse model. Only small alterations in kidney function were detected, nonetheless, they were ameliorated in A1M-injected mice. Moreover, it was concluded that A1M does not interfere with treatment.

Paper IV presents the establishment and characterization of an A1M-knockout mouse. The lack of A1M generated misfolded bikunin, which is co-expressed with A1M in the intact gene. The A1M-knockout mice also showed increased ER-stress and weight-gain. Paper V shows that the A1Mknockout
mice had fewer red blood cells (RBCs) which also varied more in size, resembling a macrocytic anemia phenotype. Paper V also concludes that A1M has antihemolytic properties, and can protect adult, fetal and murine RBCs from various stressors. Paper VI discusses the therapeutic potential of the erythrostabilizing and antihemolytic effects of A1M in different hemolytic and
erythropoietic conditions.

In conclusion, the results in these studies suggest that the protective effects of A1M towards kidneys and red blood cells may be used in cancer radiotherapy, and in hemolytic and erythropoietic medical
conditions. (Less)
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author
supervisor
opponent
  • professor Hawkins, Clare Louise, University of Copenhagen
organization
publishing date
type
Thesis
publication status
published
subject
keywords
α1-microglobulin, oxidative stress, kidneys, heme, Red blood cells, hemolysis, radiation
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2021:16
pages
102 pages
publisher
Lund University, Faculty of Medicine
defense location
Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join by Zoom: https://lu-se.zoom.us/meeting/register/u5MkdOCsqTwpHtOwIAGLbHp9Jt7TXah5mHFO
defense date
2021-03-12 09:00:00
ISSN
1652-8220
ISBN
978-91-8021-022-5
language
English
LU publication?
yes
id
cda77001-82f4-43bb-a891-4c8738aaf2f1
date added to LUP
2021-02-17 17:56:37
date last changed
2021-03-05 15:56:49
@phdthesis{cda77001-82f4-43bb-a891-4c8738aaf2f1,
  abstract     = {{Oxidative stress is defined as an imbalance between oxidants and antioxidants. The reasons behind the condition are diverse, and can result in, or contribute to, the severity of many diseases. The body has different protective mechanisms to reduce the oxidative burden, among them a protein called α<sub>1</sub>-microglobulin (A1M). A1M possesses a unique set of molecular properties enabling it to act as a<br/>radical scavenger, reductase and heme-binder. Most tissues express AMBP, the gene encoding A1M, but the liver is the main site of synthesis. A1M circulates in the blood and is catabolized in the kidneys.Therefore, two interesting sites of action for A1M are the blood and the kidneys.<br/><br/>The aim of this thesis was to investigate new therapeutic opportunities for A1M, with focus on renal and erythrocyte pathology. Paper I studied in vitro heme-induced stress in human proximal tubule<br/>epithelial cells. A1M prevented cell death, stress response and mitochondrial dysfunction. In paper II, a <sup>177</sup>Lu-DOTATATE cancer treatment mouse model showed that the radiation induced DNA breaks as well as functional and histological damage to the kidneys. The A1M-treated mice, however, showed<br/>significantly milder damage suggesting that A1M can be used as a radioprotector. Paper III investigated a <sup>177</sup>Lu-PSMA-617 prostate cancer treatment mouse model. Only small alterations in kidney function were detected, nonetheless, they were ameliorated in A1M-injected mice. Moreover, it was concluded that A1M does not interfere with treatment.<br/><br/>Paper IV presents the establishment and characterization of an A1M-knockout mouse. The lack of A1M generated misfolded bikunin, which is co-expressed with A1M in the intact gene. The A1M-knockout mice also showed increased ER-stress and weight-gain. Paper V shows that the A1Mknockout<br/>mice had fewer red blood cells (RBCs) which also varied more in size, resembling a macrocytic anemia phenotype. Paper V also concludes that A1M has antihemolytic properties, and can protect adult, fetal and murine RBCs from various stressors. Paper VI discusses the therapeutic potential of the erythrostabilizing and antihemolytic effects of A1M in different hemolytic and<br/>erythropoietic conditions.<br/><br/>In conclusion, the results in these studies suggest that the protective effects of A1M towards kidneys and red blood cells may be used in cancer radiotherapy, and in hemolytic and erythropoietic medical<br/>conditions.}},
  author       = {{Kristiansson, Amanda}},
  isbn         = {{978-91-8021-022-5}},
  issn         = {{1652-8220}},
  keywords     = {{α1-microglobulin; oxidative stress; kidneys; heme; Red blood cells; hemolysis; radiation}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{2021:16}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{α<sub>1</sub>-microglobulin – Therapeutic opportunities in kidney and erythrocyte pathology}},
  url          = {{https://lup.lub.lu.se/search/files/94221045/Amanda_Kristiansson_web.pdf}},
  year         = {{2021}},
}