NF-κB-mediated inflammation is a major pathology in kidney diseases, such as non-kidney inflammatory diseases, and rheumatoid arthritis. HIV infection in the kidney induces NF-κB activation, leading to the production of proinflammatory chemokines, cytokines, and adhesion molecules. BET bromodomain-specific inhibitors ats as more effective and safer treatments for many inflammatory diseases.
MS417 is a BET-specific bromodomain inhibitor. MS417 blocks BRD4 binding to the acetylated NF-κB, effectively attenuates NF-κB transcriptional activation of proinflammatory genes in kidney cells treated with TNFα or infected by HIV. Especially, MS417 ameliorates inflammation and kidney injury in HIV-1 transgenic mice, an animal model for HIVAN. In particular, MS417 down-regulates HIV infection-induced and NF-κB-mediated transcriptional activation of proinflammatory cytokine and chemokine genes in human renal tubular epithelial cells. MS417 also inhibits AGE-induced p65 and STAT3 acetylation and phosphorylation in podocytes.
In vivo, MS417 treatment also results in reduced proteinuria in the Tg26 mice as compared with the DMSO-treated mice, and histology analysis shows significantly reduced glomerular and tubular injury. MS417 reduces glomerulosclerosis, tubular injury, and infiltration of inflammatory cells in the kidney of Tg26 mice. Moreover, MS417 blocks acetylation-mediated association of p65 and STAT3 with BET proteins attenuates proteinuria and kidney injury in db/db mice. Furthermore, MS417 effectively downregulates NF-κB–mediated inflammatory response in kidney cells through inhibition of NF-κB–directed transcriptional activation of cytokines and attenuates kidney injury in HIV-1 transgenic mice.
Taken together, BET bromodomain inhibition represents a new therapeutic approach for treating NF-κB-mediated inflammation and kidney injury in HIV-associated nephropathy (HIVAN). MS417 is capable of attenuating kidney injury in the Tg26 mice, probably through inhibition of NF-κB-mediated inflammation.
Zhang G, et al. Down-regulation of NF-κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition. J Biol Chem. 2012 Aug 17;287(34):28840-51.