Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase

Abstract

The Connectivity Map database contains microarray signatures of gene expression derived from approximately 6000 experiments that examined the effects of approximately 1300 single drugs on several human cancer cell lines. We used these data to prioritize pairs of drugs expected to reverse the changes in gene expression observed in the kidneys of a mouse model of HIV-associated nephropathy (Tg26 mice). We predicted that the combination of an angiotensin-converting enzyme (ACE) inhibitor and a histone deacetylase inhibitor would maximally reverse the disease-associated expression of genes in the kidneys of these mice. Testing the combination of these inhibitors in Tg26 mice revealed an additive renoprotective effect, as suggested by reduction of proteinuria, improvement of renal function, and attenuation of kidney injury. Furthermore, we observed the predicted treatment-associated changes in the expression of selected genes and pathway components. In summary, these data suggest that the combination of an ACE inhibitor and a histone deacetylase inhibitor could have therapeutic potential for various kidney diseases. In addition, this study provides proof-of-concept that drug-induced expression signatures have potential use in predicting the effects of combination drug therapy.

Urinary peptidomics provides a noninvasive humanized readout of diabetic nephropathy in mice

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The primary glomerulonephritides: a systems biology approach

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Human GRK4γ 142V Variant Promotes Angiotensin II Type I Receptor–Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition

“…The apparent deleterious effect of HDAC1 inhibition by GRK4γ 142V may seem to contradict the beneficial effects of systemic HDAC inhibitors on inflammation, asthma (43), pulmonary circulation (44), oncogenesis (45), kidney disease (46), myocardial hypertrophy (47,48), and BP control (28,49). However, Class 1 HDAC inhibition may have deleterious effects on cardiac function (50).…”