Podocyte histone deacetylase activity regulates murine and human glomerular diseases
Kazunori Inoue, Geliang Gan, Maria Ciarleglio, Yan Zhang, Xuefei Tian, Christopher E. Pedigo, Corey Cavanaugh, Janet Tate, Ying Wang, Elizabeth Cross, Marwin Groener, Nathan Chai, Zhen Wang, Amy Justice, Zhenhai Zhang, Chirag R. Parikh, Francis P. Wilson, Shuta Ishibe
Kazunori Inoue, Geliang Gan, Maria Ciarleglio, Yan Zhang, Xuefei Tian, Christopher E. Pedigo, Corey Cavanaugh, Janet Tate, Ying Wang, Elizabeth Cross, Marwin Groener, Nathan Chai, Zhen Wang, Amy Justice, Zhenhai Zhang, Chirag R. Parikh, Francis P. Wilson, Shuta Ishibe
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Research Article Cell biology Nephrology

Podocyte histone deacetylase activity regulates murine and human glomerular diseases

Abstract

We identified 2 genes, histone deacetylase 1 (HDAC1) and HDAC2, contributing to the pathogenesis of proteinuric kidney diseases, the leading cause of end-stage kidney disease. mRNA expression profiling from proteinuric mouse glomeruli was linked to Connectivity Map databases, identifying HDAC1 and HDAC2 with the differentially expressed gene set reversible by HDAC inhibitors. In numerous progressive glomerular disease models, treatment with valproic acid (a class I HDAC inhibitor) or SAHA (a pan-HDAC inhibitor) mitigated the degree of proteinuria and glomerulosclerosis, leading to a striking increase in survival. Podocyte HDAC1 and HDAC2 activities were increased in mice podocytopathy models, and podocyte-associated Hdac1 and Hdac2 genetic ablation improved proteinuria and glomerulosclerosis. Podocyte early growth response 1 (EGR1) was increased in proteinuric patients and mice in an HDAC1- and HDAC2-dependent manner. Loss of EGR1 in mice reduced proteinuria and glomerulosclerosis. Longitudinal analysis of the multicenter Veterans Aging Cohort Study demonstrated a 30% reduction in mean annual loss of estimated glomerular filtration rate, and this effect was more pronounced in proteinuric patients receiving valproic acid. These results strongly suggest that inhibition of HDAC1 and HDAC2 activities may suppress the progression of human proteinuric kidney diseases through the regulation of EGR1.

Authors

Kazunori Inoue, Geliang Gan, Maria Ciarleglio, Yan Zhang, Xuefei Tian, Christopher E. Pedigo, Corey Cavanaugh, Janet Tate, Ying Wang, Elizabeth Cross, Marwin Groener, Nathan Chai, Zhen Wang, Amy Justice, Zhenhai Zhang, Chirag R. Parikh, Francis P. Wilson, Shuta Ishibe

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Figure 7

VPA treatment mitigates CREB-mediated EGR1 upregulation in primary podocytes treated with LPS or PS.

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VPA treatment mitigates CREB-mediated EGR1 upregulation in primary podoc...
(A) Representative immunoblots of EGR1 and WT1 in primary podocytes with or without LPS or PS, treated or not treated with VPA or SAHA. (B and C) Quantification of EGR1 immunoblots in primary podocytes with LPS (B) or PS (C) treated or not treated with VPA or SAHA. *P < 0.05 vs. control, #P < 0.05 vs. LPS- or PS-treated primary podocytes; n = 3. (D and E) ChIP assay using CREB antibody and primer sets for Egr1 promoter in primary podocytes with LPS (D) or PS (E) treated or not treated with VPA or SAHA. DNA binding was determined by PCR. *P < 0.05 vs. control, #P < 0.05 vs. LPS- or PS-treated primary podocytes; n = 3. (F) Representative immunoblots of phosphorylated CREB (p-CREB), CREB, and WT1 in LPS- or PS-treated primary podocytes with or without VPA or SAHA. (G and H) Quantification of p-CREB immunoblots in primary podocytes with LPS (G) or PS (H) treated or not treated with VPA or SAHA. *P < 0.05 vs. control, #P < 0.05 vs. LPS- or PS-treated primary podocytes; n = 3. (B–E, G, and H) Statistically analyzed by 1-way ANOVA with Dunnett’s correction.