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Podocyte histone deacetylase activity regulates murine and human glomerular diseases
Kazunori Inoue, … , Francis P. Wilson, Shuta Ishibe
Kazunori Inoue, … , Francis P. Wilson, Shuta Ishibe
Published February 18, 2019
Citation Information: J Clin Invest. 2019;129(3):1295-1313. https://doi.org/10.1172/JCI124030.
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Research Article Cell biology Nephrology

Podocyte histone deacetylase activity regulates murine and human glomerular diseases

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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 1

Doxycycline-inducible podocyte-specific Tln1-KO mice have massive proteinuria with kidney failure.

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Doxycycline-inducible podocyte-specific Tln1-KO mice have massive protei...
(A) Representative glomerular immunofluorescence images of talin-1 (green) and nephrin (red) in doxycycline-induced (Dox-induced) control and Tln1fl/fl Pod-rtTA TetO-Cre mice. Scale bar: 10 μm. (B) Quantification of urine albumin/creatinine ratio in control and Tln1fl/fl Pod-rtTA TetO-Cre mice at 0, 2, and 4 weeks after completion of Dox induction. *P < 0.05 vs. control; n = 5. (C) Plasma creatinine (Cr) levels in control and Tln1fl/fl Pod-rtTA TetO-Cre mice treated with Dox at 0 and 4 weeks after completion of Dox induction. *P < 0.05 vs. control; n = 5. (D) Representative light microscope images (H&E, periodic acid–Schiff [PAS], and trichrome) of Dox-induced control and Tln1fl/fl Pod-rtTA TetO-Cre mouse glomeruli. Arrowheads show mesangial matrix deposition and mesangial cell proliferation. Scale bar: 25 μm. (E) Representative trichrome staining in control and Tln1fl/fl Pod-rtTA TetO-Cre mouse kidneys at representative time points. Arrowheads depict dilated tubules and proteinaceous casts, and arrows display interstitial fibrosis. Scale bar: 50 μm. (F) Representative transmission electron micrograph (TEM) in control and Tln1fl/fl Pod-rtTA TetO-Cre mouse foot processes after Dox induction. Arrowheads depict podocyte foot process effacement. Scale bar: 1 μm. (G) Quantification of glomerulosclerosis in D. *P < 0.05 vs. control. (H) Quantification of interstitial fibrosis in E. *P < 0.05 vs. control. (I) Quantification of foot processes in F. *P < 0.05 vs. control. (J) Quantification of WT1-positive number per glomerulus in control and Tln1fl/fl Pod-rtTA TetO-Cre mice treated with Dox at 0 and 4 weeks after completion of Dox induction. *P < 0.05 vs. control; n = 3. (B, C, and G–J) Statistically analyzed by 1-way ANOVA with Dunnett’s correction.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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