Murine Double Minute-2 Inhibition Ameliorates Established Crescentic Glomerulonephritis.
Rapidly progressive glomerulonephritis is characterized by glomerular necroinflammation and crescent formation. Its treatment includes unspecific and toxic agents; therefore, the identification of novel therapeutic targets is required. The E3-ubiquitin ligase murine double minute (MDM)-2 is a nonredundant element of NF-κB signaling and the negative regulator of tumor suppressor gene TP53-mediated cell cycle arrest and cell death. We hypothesized that the MDM2 would drive crescentic glomerulonephritis by NF-κB-dependent glomerular inflammation and by p53-dependent parietal epithelial cell hyperproliferation. Indeed, the pre-emptive MDM2 blockade by nutlin-3a ameliorated all aspects of crescentic glomerulonephritis. MDM2 inhibition had identical protective effects in Trp53-deficient mice, with the exception of crescent formation, which was not influenced by nutlin-3a treatment. In vitro experiments confirmed the contribution of MDM2 for induction of NF-κB-dependent cytokines in murine glomerular endothelial cells and for p53-dependent parietal epithelial cell proliferation. To evaluate MDM2 blockade as a potential therapeutic intervention in rapidly progressive glomerulonephritis, we treated mice with established glomerulonephritis with nutlin-3a. Delayed onset of nutlin-3a treatment was equally protective as the pre-emptive treatment in abrogating crescentic glomerulonephritis. Together, the pathogenic effects of MDM2 are twofold, that is, p53-independent NF-κB activation increasing intraglomerular inflammation and p53-dependent parietal epithelial cell hyperplasia and crescent formation. We therefore propose MDM2 blockade as a potential novel therapeutic strategy in rapidly progressive glomerulonephritis.
Division of Nephrology, Medizinische Klinik und Poliklinik IV, University Hospital of Ludwig-Maximilians-University, Munich, Germany.
Shrikant R
SR
Mulay
Division of Nephrology, Medizinische Klinik und Poliklinik IV, University Hospital of Ludwig-Maximilians-University, Munich, Germany.
Simone
S
Romoli
Division of Nephrology, Medizinische Klinik und Poliklinik IV, University Hospital of Ludwig-Maximilians-University, Munich, Germany.
Jyaysi
J
Desai
Division of Nephrology, Medizinische Klinik und Poliklinik IV, University Hospital of Ludwig-Maximilians-University, Munich, Germany.
Mohammad Mohsen
MM
Honarpisheh
Division of Nephrology, Medizinische Klinik und Poliklinik IV, University Hospital of Ludwig-Maximilians-University, Munich, Germany.
Santhosh V
SV
Kumar
Division of Nephrology, Medizinische Klinik und Poliklinik IV, University Hospital of Ludwig-Maximilians-University, Munich, Germany.
Hans-Joachim
HJ
Anders
Division of Nephrology, Medizinische Klinik und Poliklinik IV, University Hospital of Ludwig-Maximilians-University, Munich, Germany. Electronic address: dana.thomasova@med.uni-muenchen.de.
Dana
D
Thomasova
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000378:metabolism / Q000473:pathology*; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2