Murine double minute-2 (MDM2), an E3 ligase that regulates the cell cycle and inflammation, is highly expressed in podocytes. In podocyte injury, MDM2 drives podocyte loss by mitotic catastrophe, but the function of MDM2 in resting podocytes has not been explored. Here, we investigated the effects of podocyte MDM2 deletion in vitro and in vivo. In vitro, MDM2 knockdown by siRNA caused increased expression of p53 and podocyte death, which was completely rescued by coknockdown of p53. Apoptosis, pyroptosis, pyronecrosis, necroptosis, ferroptosis, and parthanatos were excluded as modes of occurrence for this p53-overactivationrelated cell death (here referred to as podoptosis). Podoptosis was associated with cytoplasmic vacuolization, endoplasmic reticulum stress, and dysregulated autophagy (previously described as paraptosis). MDM2 knockdown caused podocyte loss and proteinuria in a zebrafish model, which was consistent with the phenotype of podocyte-specific MDM2-knockout mice that also showed the aforementioned ultrastructual podocyte abnormalities before and during progressive glomerulosclerosis. The phenotype of both animal models was entirely rescued by codeletion of p53. We conclude that MDM2 maintains homeostasis and long-term survival in podocytes by preventing podoptosis, a p53-regulated form of cell death with unspecific features previously classified as paraptosis.

Background: Shortly after the gel test was introduced into routine immunohaemato-logy, an increased percentage of patients were reported to show a positive auto-control in the indirect antiglobulin test (IAT) of uncertain significance as the direct antiglobulin test (DAT) in the tube technique was negative. Materials and Methods: In our study 13,280 randomized patient blood samples were screened and additional investigations carried out including an analysis of patient histories in the 97 blood samples that were auto-control positive in the gel test. Results: In 87.4%, a re-testing with polyspecific antiglobulin serum (83.2% with anti-IgG) showed positive results in contrast to only 52.9% re-tested by the tube test. Neither nonspecificity nor cold agglutinins were significant. None of the patients examined showed any signs of haemolysis exept for one with pernicious anaemia. We concluded that the increased number of positive auto-controls and DATs is due to the greater sensitivity of the gel test and thus the detection of minute quantities of specific cell-bound IgG molecules, i. e. warm auto-antibodies or drug-induced antibodies. Conclusion: Prior to transfusion, a positive result should be confirmed by a tube DAT. If this test is negative and there is no history of a previous transfusion or of haemolysis, the transfusion should not be delayed by carrying out further time-consuming investigations.Schlüsselwòrter

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