MDM2 (murine double minute-2) links inflammation and tubular cell healing during acute kidney injury in mice.
Murine double minute (MDM)-2, an E3 ubiquitin ligase, promotes cancer cell survival and growth, by degrading the cell cycle regulator p53. Antagonism of MDM2 by the small-molecule cis-imidazoline nutlin analogs is under current study for cancer therapy. To test whether MDM2 also promotes regenerative cell growth, we determined the effects of nutlin-3a on tubule cell healing during postischemic acute kidney injury (AKI). Treatment with nutlin-3a impaired tubular cell regeneration during postischemic AKI in wild-type mice in a p53-dependent manner; however, MDM2 blockade also prevented tubular necrosis by suppressing sterile inflammation during the early postischemic phase. This effect also occurred in p53 knockout mice, indicating a second, proinflammatory, p53-independent role for MDM2 in AKI. In vitro experiments confirmed that MDM2 is required to induce mRNA expression and secretion of NFκB-dependent cytokines upon Toll-like receptor stimulation by enhanced binding of NFκB to cytokine promoter-binding sites. Thus, MDM2 links inflammation and epithelial healing during AKI. These additional biological functions need to be regarded when considering MDM2 inhibition therapy.
Renal Division, Medizinische Klinik and Poliklinik IV, Universität München, Germany.
Shrikant R
SR
Mulay
Dana
D
Thomasova
Mi
M
Ryu
Hans-Joachim
HJ
Anders
D058186:Acute Kidney Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007093:Imidazoles / Q000008:administration & dosage; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007684:Kidney Tubules / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D010879:Piperazines / Q000008:administration & dosage; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012038:Regeneration; D015427:Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing
D016207:Cytokines; D007093:Imidazoles; D018836:Inflammation Mediators; D016328:NF-kappa B; D010879:Piperazines; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2