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

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

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Abstract

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
Pages (from-to)539-552
Number of pages14
JournalJournal of Clinical Investigation
Volume111
Issue number4
DOIs
StatePublished - Feb 1 2003

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trichostatin A
Histone Deacetylase Inhibitors
Histone Deacetylases
Kidney
Histones
Systemic Lupus Erythematosus
Hydroxamic Acids
Interleukin-12
Acetylation
Glomerulonephritis
Proteinuria
Interleukin-10
Genes
Chromatin
Interleukin-6
Down-Regulation
Spleen
Cytokines
Gene Expression
Weights and Measures

ASJC Scopus subject areas

  • Medicine(all)

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Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. / Mishra, Nilamadhab; Reilly, Christopher M.; Brown, Doris R.; Ruiz, Phillip; Gilkeson, Gary S.

In: Journal of Clinical Investigation, Vol. 111, No. 4, 01.02.2003, p. 539-552.

Research output: Contribution to journalArticle

Mishra, Nilamadhab ; Reilly, Christopher M. ; Brown, Doris R. ; Ruiz, Phillip ; Gilkeson, Gary S. / Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. In: Journal of Clinical Investigation. 2003 ; Vol. 111, No. 4. pp. 539-552.
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