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.
MASSON-TRICHROM (MTS)-FÄRBUNG 2.2.5 HÄMATOXYLIN-EOSIN (HE)-FÄRBUNG NACH MAYER 2.2.6 PERIODIC-ACID-SCHIFFS (PAS)-FÄRBUNG 2.2.7 ZELLKULTUR 1. Einleitung 2.2.8 IMMUNOPREZIPITATION METHYLIERTER UND HYDROXYMETHYLIERTER DNA (MEDIP/HMEDIP) 2.2.9 WILDTYP-MAUSLINIE 2.2.10 AUSWERTUNG 3. ERGEBNISSE 3.1 IN-VITRO-STIMULATIONSVERSUCH AN PRIMÄREN FIBROBLASTENKULTUREN 3.2 EPIGENETISCHE THERAPIE MIT NIEDRIG-DOSIERTEM HYDRALAZIN VERRINGERT DEN ÜBERGANG VOM AKUTEN INS CHRONISCHE NIERENVERSAGEN UND DIE INTRARENALE FIBROBLASTENAKKUMULATION 3.3 ÜBERGANG VOM AKUTEN INS CHRONISCHE NIERENVERSAGEN UNTER SCHWERER IRI IST MIT RASAL1-PROMOTERMETHYLIERUNG ASSOZIIERT 3.3.1 ABERRANTE RASAL1-PROMOTERMETHYLIERUNG ALS EPIGENETISCHER FAKTOR DERFIBROSEREGULATION 3.3.2 NACHWEIS EINES TET3-VERMITTELTEN DEMETHYLIERUNGSMECHANISMUS UNTER NIEDRIG DOSIERTER HYDRALAZINTHERAPIE 4. DISKUSSION 4.1 RASAL1-PROMOTERMETHYLIERUNG ALS SCHLÜSSELROLLE DER PROGRESSION VOM AKUTEN INS CHRONISCHE NIERENVERSAGEN 4.2 HYDRALAZIN ALS THERAPEUTISCHE INTERVENTION MIT INDUKTION TET3-VERMITTELTER HYDROXYMETHYLIERUNG 4.3 DARSTELLUNG DER KORRELATION VON FIBROSIERUNGSKOMPONENTEN NIERENKRANKER PATIENTEN 4.4 MEDIKAMENTÖSER EINGRIFF INS RENIN-ANGIOTENSIN-ALDOSTERON-SYSTEM UND SEIN EINFLUSS AUF DAS AKUTE NIERENVERSAGEN
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