Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse

Nilamadhab Mishra, Christopher M. Reilly, Doris R. Brown, Phil Ruiz, Gary S. Gilkeson

Research output: Contribution to journalArticlepeer-review

324 Scopus citations


Studies in human systemic lupus erythematosus (SLE) suggest a possible role for histone deacetylases (HDACs) in skewed gene expression and disease pathogenesis. We used the MRL-lpr/lpr murine model of lupus to demonstrate that HDACs play a key role in the heightened levels of both Th1 and Th2 cytokine expression that contribute to disease. The availability of specific HDAC inhibitors (HDIs) such as trichostatin A (TSA) and suberonylanilide hydroxamic acid (SAHA) permits the study of the role of HDACs in gene regulation. Our results indicate that HDIs downregulate IL-12, IFN-γ, IL-6, and IL-10 mRNA and protein levels in MRL-lpr/lpr splenocytes. This effect on gene transcription is associated with an increased accumulation of acetylated histones H3 and H4 in total cellular chromatin. To elucidate the in vivo effects of TSA on lupuslike disease, we treated MRL-lpr/lpr mice with TSA (0.5 mg/kg/d) for 5 weeks. Compared with vehicle-treated control mice, TSA-treated mice exhibited a significant reduction in proteinuria, glomerulonephritis, and spleen weight. Taken together, these findings suggest that increased expression of HDACs leading to an altered state of histone acetylation may be of pathologic significance in MRL-lpr/lpr mice. In addition, TSA or other HDIs may have therapeutic benefit in the treatment of SLE.

Original languageEnglish (US)
Pages (from-to)539-552
Number of pages14
JournalJournal of Clinical Investigation
Issue number4
StatePublished - Feb 2003

ASJC Scopus subject areas

  • Medicine(all)


Dive into the research topics of 'Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse'. Together they form a unique fingerprint.

Cite this