Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease
Syamantak Majumder, … , Ferhan S. Siddiqi, Andrew Advani
Syamantak Majumder, … , Ferhan S. Siddiqi, Andrew Advani
Published December 11, 2017
Citation Information: J Clin Invest. 2018;128(1):483-499. https://doi.org/10.1172/JCI95946.
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Research Article Endocrinology Nephrology

Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease

Abstract

Histone protein modifications control fate determination during normal development and dedifferentiation during disease. Here, we set out to determine the extent to which dynamic changes to histones affect the differentiated phenotype of ordinarily quiescent adult glomerular podocytes. To do this, we examined the consequences of shifting the balance of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark in podocytes. Adriamycin nephrotoxicity and subtotal nephrectomy (SNx) studies indicated that deletion of the histone methylating enzyme EZH2 from podocytes decreased H3K27me3 levels and sensitized mice to glomerular disease. H3K27me3 was enriched at the promoter region of the Notch ligand Jag1 in podocytes, and derepression of Jag1 by EZH2 inhibition or knockdown facilitated podocyte dedifferentiation. Conversely, inhibition of the Jumonji C domain–containing demethylases Jmjd3 and UTX increased the H3K27me3 content of podocytes and attenuated glomerular disease in adriamycin nephrotoxicity, SNx, and diabetes. Podocytes in glomeruli from humans with focal segmental glomerulosclerosis or diabetic nephropathy exhibited diminished H3K27me3 and heightened UTX content. Analogous to human disease, inhibition of Jmjd3 and UTX abated nephropathy progression in mice with established glomerular injury and reduced H3K27me3 levels. Together, these findings indicate that ostensibly stable chromatin modifications can be dynamically regulated in quiescent cells and that epigenetic reprogramming can improve outcomes in glomerular disease by repressing the reactivation of developmental pathways.

Authors

Syamantak Majumder, Karina Thieme, Sri N. Batchu, Tamadher A. Alghamdi, Bridgit B. Bowskill, M. Golam Kabir, Youan Liu, Suzanne L. Advani, Kathryn E. White, Laurette Geldenhuys, Karthik K. Tennankore, Penelope Poyah, Ferhan S. Siddiqi, Andrew Advani

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Figure 4

Inhibition of Jmjd3 and UTX attenuates renal injury in diabetic mice.

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Inhibition of Jmjd3 and UTX attenuates renal injury in diabetic mice. (A...
(A) Body weight, (B) kidney weight, (C) blood glucose, (D) HbA1c, (E) urine volume, and (F) 24-hour urine albumin excretion in nondiabetic db/m mice and diabetic db/db mice treated with vehicle or GSK-J4 (10 mg/kg) i.p. thrice weekly for 10 weeks (db/m plus vehicle, n = 12; db/m plus GSK-J4, n = 11; db/db plus vehicle, n = 10; db/db plus GSK-J4, n = 9). (G) Transmission electron micrographs and podocyte foot process widths for db/m and db/db mice treated with vehicle or GSK-J4 (db/m plus vehicle, n = 4; db/m plus GSK-J4, n = 4; db/db plus vehicle, n = 4; db/db plus GSK-J4, n = 4). Arrows mark areas of foot process widening in the glomerulus of the vehicle-treated db/db mouse. Scale bars: 2 μm. (H) Immunofluorescence to detect the podocyte marker nephrin and Jagged-1 in glomeruli from db/m and db/db mice treated with vehicle or GSK-J4 (db/m plus vehicle, n = 12; db/m plus GSK-J4, n = 11; db/db plus vehicle, n = 9; db/db plus GSK-J4, n = 9). DAPI staining is shown in blue. Original magnification, ×630. Values represent the mean ± SEM. *P < 0.05, **P < 0.01, and ****P < 0.0001, by 1-way ANOVA followed by Fisher’s LSD post-hoc test.