Supplementary Material for: Untargeted DNA-Demethylation Therapy Neither Prevents Nor Attenuates Ischemia-Reperfusion-Induced Renal Fibrosis
Vervaet B.A.
Moonen L.
Godderis L.
Poels K.
D'Haese P.C.
10.6084/m9.figshare.5249158.v1
https://karger.figshare.com/articles/dataset/Supplementary_Material_for_Untargeted_DNA-Demethylation_Therapy_Neither_Prevents_Nor_Attenuates_Ischemia-Reperfusion-Induced_Renal_Fibrosis/5249158
<p><b><i>Background:</i></b> Current treatment options for chronic
kidney disease (CKD) are limited and their focus is on slowing its
progression by addressing comorbidities. Fibrosis, the common
histopathological process in CKD, is a major therapeutic research
target. In CKD, fibroblasts are terminally activated due to alterations
in their DNA-methylation pattern, particularly hypermethylation.
Preventing the copying of pathological DNA-methylation patterns in
proliferating fibroblasts could be a new effective therapeutic strategy
for treating CKD. <b><i>Methods:</i></b> To evaluate the therapeutic
effect of short-term treatment with the DNA-methyltransferase
(DNMT)-inhibitor decitabine on fibrosis (either developing or already
established), male C57Bl/6 mice underwent warm unilateral
ischemia-reperfusion injury. Respectively 3 days, 3 and 6 weeks after
surgery, decitabine treatment (0.25 mg/kg) was initiated for 10 days
after which animals were followed up to 12 weeks after ischemia. The
efficacy of therapy on fibrosis was evaluated by <i>collagen I</i> and <i>tgfβ</i>
gene expression and histological quantification of collagen I staining.
In addition, the effect of decitabine treatment on tubular injury (<i>Kim-1</i>, <i>Ngal</i>), inflammation (<i>TNFa</i>, <i>IL6</i>), DNA-methyltransferases (<i>Dnmt1, 3a, and 3b</i>), and global methylation status was determined. <b><i>Results:</i></b>
Following ischemia there was a significant increase in fibrotic,
injury, and inflammatory markers as well as an increase of the various <i>dnmts</i>.
Although decitabine treatment transiently increased renal injury and
had a moderately decreasing effect on dnmt expression and on global
DNA-methylation upon immediate treatment, none of the treatment regimens
succeeded in preventing, attenuating, or diminishing fibrosis in the
long run. <b><i>Conclusion:</i></b> Administration of untargeted
nucleoside analogues seems unsuitable as a first-line treatment option
in developing or established CKD.</p>
2017-07-27 11:22:51
Acute kidney injury-to-chronic kidney disease
Ischemia-reperfusion
Fibrosis
dna-methylation
Decitabine