Losartan reverses permissive epigenetic changes in renal glomeruli of diabetic
db/db mice.
Authors Reddy MA, Sumanth P, Lanting L, Yuan H, Wang M, Mar D, Alpers CE, Bomsztyk K,
Natarajan R
Submitted By Submitted Externally on 12/20/2013
Status Published
Journal Kidney international
Year 2013
Date Published 10/2/2013
Volume : Pages 85 : 362 - 373
PubMed Reference 24088954
Abstract Epigenetic mechanisms such as chromatin histone H3 lysine methylation and
acetylation have been implicated in diabetic vascular complications. However,
histone modification profiles at pathologic genes associated with diabetic
nephropathy in vivo and their regulation by the angiotensin II type 1 receptor
(AT1R) are not clear. Here we tested whether treatment of type 2 diabetic db/db
mice with the AT1R blocker losartan not only ameliorates diabetic nephropathy,
but also reverses epigenetic changes. As expected, the db/db mice had increased
blood pressure, mesangial hypertrophy, proteinuria, and glomerular expression of
RAGE and PAI-1 vs. control db/+ mice. This was associated with increased RNA
polymerase II recruitment and permissive histone marks as well as decreased
repressive histone marks at these genes, and altered expression of relevant
histone modification enzymes. Increased MCP-1 mRNA levels were not associated
with such epigenetic changes, suggesting post-transcriptional regulation.
Losartan attenuated key parameters of diabetic nephropathy and gene expression,
and reversed some but not all the epigenetic changes in db/db mice. Losartan
also attenuated increased H3K9/14Ac at RAGE, PAI-1, and MCP-1 promoters in
mesangial cells cultured under diabetic conditions. Our results provide novel
information about the chromatin state at key pathologic genes in vivo in
diabetic nephropathy mediated in part by AT1R. Thus, combination therapies
targeting epigenetic regulators and AT1R could be evaluated for more effective
treatment of diabetic nephropathy.Kidney International advance online
publication, 2 October 2013; doi:10.1038/ki.2013.387.

Investigators with authorship
Charles AlpersUniversity of Washington
Karol BomsztykUniversity of Washington