Murine Double Minute-2 Inhibition Ameliorates Established Crescentic Glomerulonephritis.

Murine Double Minute-2 Inhibition Ameliorates Established Crescentic Glomerulonephritis. Am J Pathol. 2016 Apr 18; Authors: Mulay SR, Romoli S, Desai J, Honarpisheh MM, Kumar SV, Anders HJ, Thomasova D Abstract 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 glomerulo...
Source: The American Journal of Pathology - Category: Pathology Authors: Tags: Am J Pathol Source Type: research