Low-dose hydralazine prevents fibrosis in a murine model of acute kidney injury-to-chronic kidney disease progression.
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.
Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany.
Björn
B
Tampe
Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany.
Ulrike
U
Steinle
Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany.
Désirée
D
Tampe
Department of Cancer Biology and the Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Julienne L
JL
Carstens
Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany.
Peter
P
Korsten
Department of Cardiology and Pneumology, Göttingen University Medical Center, Georg August University, Göttingen, Germany; German Center for Cardiovascular Research, Göttingen, Germany.
Elisabeth M
EM
Zeisberg
Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany.
Gerhard A
GA
Müller
Department of Cancer Biology and the Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Raghu
R
Kalluri
Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany; German Center for Cardiovascular Research, Göttingen, Germany. Electronic address: mzeisberg@med.uni-goettingen.de.
Michael
M
Zeisberg
D058186:Acute Kidney Injury / Q000188:drug therapy*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D049308:Dioxygenases; D004195:Disease Models, Animal; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D020690:GTPase-Activating Proteins / Q000235:genetics*; D006801:Humans; D006830:Hydralazine / Q000008:administration & dosage / Q000627:therapeutic use*; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017257:Ramipril / Q000494:pharmacology; D065667:Renal Elimination / Q000187:drug effects; D051436:Renal Insufficiency, Chronic / Q000517:prevention & control*; D015427:Reperfusion Injury / Q000150:complications; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*
D000806:Angiotensin-Converting Enzyme Inhibitors; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D011518:Proto-Oncogene Proteins; C580923:RASAL1 protein, human; C000590956:RASAL1 protein, mouse; D014665:Vasodilator Agents; D006830:Hydralazine; D049308:Dioxygenases; C551915:Tet3 protein, mouse; D017257:Ramipril
AKI-to-CKD-progression; Aberrant DNA methylation; CpG promoter methylation; RASAL1; TET3 hydroxylase; epigenetic; kidney injury; low-dose hydralazine; renal fibrosis; reno-protection