TY - JOUR
T1 - Low-dose hydralazine prevents fibrosis in a murine model of acute kidney injury–to–chronic kidney disease progression
AU - Tampe, Björn
AU - Steinle, Ulrike
AU - Tampe, Désirée
AU - Carstens, Julienne L.
AU - Korsten, Peter
AU - Zeisberg, Elisabeth M.
AU - Müller, Gerhard A.
AU - Kalluri, Raghu
AU - Zeisberg, Michael
N1 - Publisher Copyright:
© 2016 International Society of Nephrology
PY - 2017/1/1
Y1 - 2017/1/1
N2 - Acute kidney injury (AKI) and progressive chronic kidney disease (CKD) are intrinsically tied syndromes. In this regard, the acutely injured kidney often does not achieve its full regenerative capacity and AKI directly transitions into progressive CKD associated with tubulointerstitial fibrosis. Underlying mechanisms of such AKI-to-CKD progression are still incompletely understood and specific therapeutic interventions are still elusive. Because epigenetic modifications play a role in maintaining tissue fibrosis, we used a murine model of ischemia-reperfusion injury to determine whether aberrant promoter methylation of RASAL1 contributes causally to the switch between physiological regeneration and tubulointerstitial fibrogenesis, a hallmark of AKI-to-CKD progression. It is known that the antihypertensive drug hydralazine has demethylating activity, and that its optimum demethylating activity occurs at concentrations below blood pressure–lowering doses. Administration of low-dose hydralazine effectively induced expression of hydroxylase TET3, which catalyzed RASAL1 hydroxymethylation and subsequent RASAL1 promoter demethylation. Hydralazine-induced CpG promoter demethylation subsequently attenuated renal fibrosis and preserved excretory renal function independent of its blood pressure–lowering effects. In comparison, RASAL1 demethylation and inhibition of tubulointerstitial fibrosis was not detected upon administration of the angiotensin-converting enzyme inhibitor Ramipril in this model. Thus, RASAL1 promoter methylation and subsequent transcriptional RASAL1 suppression plays a causal role in AKI-to-CKD progression.
AB - Acute kidney injury (AKI) and progressive chronic kidney disease (CKD) are intrinsically tied syndromes. In this regard, the acutely injured kidney often does not achieve its full regenerative capacity and AKI directly transitions into progressive CKD associated with tubulointerstitial fibrosis. Underlying mechanisms of such AKI-to-CKD progression are still incompletely understood and specific therapeutic interventions are still elusive. Because epigenetic modifications play a role in maintaining tissue fibrosis, we used a murine model of ischemia-reperfusion injury to determine whether aberrant promoter methylation of RASAL1 contributes causally to the switch between physiological regeneration and tubulointerstitial fibrogenesis, a hallmark of AKI-to-CKD progression. It is known that the antihypertensive drug hydralazine has demethylating activity, and that its optimum demethylating activity occurs at concentrations below blood pressure–lowering doses. Administration of low-dose hydralazine effectively induced expression of hydroxylase TET3, which catalyzed RASAL1 hydroxymethylation and subsequent RASAL1 promoter demethylation. Hydralazine-induced CpG promoter demethylation subsequently attenuated renal fibrosis and preserved excretory renal function independent of its blood pressure–lowering effects. In comparison, RASAL1 demethylation and inhibition of tubulointerstitial fibrosis was not detected upon administration of the angiotensin-converting enzyme inhibitor Ramipril in this model. Thus, RASAL1 promoter methylation and subsequent transcriptional RASAL1 suppression plays a causal role in AKI-to-CKD progression.
KW - AKI-to-CKD-progression
KW - Aberrant DNA methylation
KW - CpG promoter methylation
KW - RASAL1
KW - TET3 hydroxylase
KW - epigenetic
KW - kidney injury
KW - low-dose hydralazine
KW - renal fibrosis
KW - reno-protection
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U2 - 10.1016/j.kint.2016.07.042
DO - 10.1016/j.kint.2016.07.042
M3 - Article
C2 - 27692563
AN - SCOPUS:85006371721
SN - 0085-2538
VL - 91
SP - 157
EP - 176
JO - Kidney International
JF - Kidney International
IS - 1
ER -