Address correspondence to: Andrew Advani, St. Michael’s Hospital, 6-151, 61 Queen Street East, Toronto, Ontario, Canada. M5C 2T2. Phone: 416.864.6060, ext. 8413; Email: ac.hms@ainavda.

Authorship note: S. Majumder and K. Thieme contributed equally to this work.

Karina Thieme: rb.psu@emeiht.anirak; Youan Liu: ac.hms@oYuiL; Laurette Geldenhuys: ac.htlaehsn@DMsyuhnedleg.etterual; Penelope Poyah: ac.htlaehsn@hayop.epoleneP; Andrew Advani: ac.hms@ainavdaAddress correspondence to: Andrew Advani, St. Michael’s Hospital, 6-151, 61 Queen Street East, Toronto, Ontario, Canada. M5C 2T2. Phone: 416.864.6060, ext. 8413; Email: ac.hms@ainavda.Authorship note: S. Majumder and K. Thieme contributed equally to this work.

Received 2017 Jun 29; Accepted 2017 Oct 31.

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.

Keywords: Endocrinology, Nephrology

Keywords: Chronic kidney disease, Diabetes, Epigenetics

Abstract

Acknowledgments

The authors thank Kryski Biomedia for the artwork. These studies were supported by a Biomedical Research Grant from the Kidney Foundation of Canada and an Operating Grant from Diabetes Canada (OG-3-14-4502-AA) and in part by Grant-in-Aid funding from the Heart and Stroke Foundation of Canada (G-14-0005877, to AA) and a Canadian Institutes of Health Research Operating Grant (MOP-133631, to AA). SM was supported by a Diabetes Canada Postdoctoral Fellowship. KT was supported by a Research Internship Abroad grant from the Sao Paulo Research Foundation (Fapesp 2016/04591-1). SNB is supported by a Keenan Family Foundation KRESCENT Postdoctoral Fellowship Award and was supported by a Heart and Stroke/Richard Lewar Center of Excellence Fellowship Award and a Banting and Best Diabetes Centre Hugh Sellers Postdoctoral Fellowship. TAA is supported by a King Abdullah Foreign Scholarship. AA is a recipient of a Diabetes Investigator Award from Diabetes Canada.

Acknowledgments

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Footnotes

S. Majumder’s present address is: Department of Biological Sciences, Birla Institute of Technology and Sciences (BITS), Pilani, Rajasthan, India.

Conflict of interest: A. Advani has received research support from Boehringer Ingelheim and AstraZeneca and is listed as an inventor on a patent application (WO 2015/128453) submitted by Boehringer Ingelheim.

Reference information: J Clin Invest. 2018;128(1):483–499.https://doi.org/10.1172/JCI95946.

Footnotes

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