Upregulation of HIF‐1α contributes to complement activation in transplantation‐associated thrombotic microangiopathy

Summary Transplantation‐associated thrombotic microangiopathy (TA‐TMA) is a severe complication of haematopoietic stem cell transplantation (HSCT). Complement activation is involved in the development of TA‐TMA. However, the underlying mechanism is unclear. Therefore, 21 samples of TA‐TMA and 1:1 matched controls were measured for hypoxia‐inducible factor‐1α (HIF‐1α) and complement protein. The mechanism was investigated both in vitro and in vivo . In this study, we found that levels of HIF‐1α were significantly higher in TA‐TMA patients than that in non‐TA‐TMA controls. Upregulation of HIF‐1α induced an increase in membrane‐bound complement C3 and dysfunction of human umbilical vein endothelial cells (HUVECs) in vitro . Increasing HIF‐1α in vivo led to C3 and C5b‐9 deposition in the glomerular endothelial capillary complex, thrombocytopenia, anaemia, and increased serum lactate dehydrogenase (LDH) levels in wild‐type (WT) but not in C3 −/− mice subjected to HSCT. High platelet aggregation in peripheral blood and CD41‐positive microthrombi in the kidney were also found in dimethyloxallyl glycine (DMOG)‐treated mice, recapitulating the TA‐TMA phenotype seen in patients. Comprehensive analysis, including DNA array, luciferase reporter assay, chromatin immunoprecipitation (ChIP)‐seq, and quantitative polymerase chain reaction (PCR), revealed that HIF‐1α interacted with the promoter of complement factor H (CFH) to inhibit its transcription. Decreased CFH led to complement activation in endothelial cells.