Upregulation of HIF-1 alpha contributes to complement activation in transplantation-associated thrombotic microangiopathy

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-1 alpha (HIF-1 alpha) and complement protein. The mechanism was investigated both in vitro and in vivo. In this study, we found that levels of HIF-1 alpha were significantly higher in TA-TMA patients than that in non-TA-TMA controls. Upregulation of HIF-1 alpha induced an increase in membrane-bound complement C3 and dysfunction of human umbilical vein endothelial cells (HUVECs) in vitro. Increasing HIF-1 alpha 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-1 alpha interacted with the promoter of complement factor H (CFH) to inhibit its transcription. Decreased CFH led to complement activation in endothelial cells.