α1-microglobulin – Therapeutic opportunities in kidney and erythrocyte pathology

Sammanfattning: 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 aradical 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 tubuleepithelial 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, showedsignificantly 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 A1Mknockoutmice 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 anderythropoietic 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 medicalconditions.