title: miR-182-5p Inhibition Ameliorates Ischemic Acute Kidney Injury.
abstract: Acute kidney injury (AKI) remains a major clinical event with high mortality rates. We previously identified renal miR-182 as the main driver of post-transplantation AKI. Therefore, we tested the causal inference of miR-182 by inhibiting its renal expression in vivo. In 45 rats AKI was induced by right nephrectomy and contralateral clamping of the renal pedicle for 40 minutes. Systemically administered antisense oligonucleotide (ASO) inhibited miR-182 in the kidneys up to 96 hours. The maximum creatinine elevation was on day 2 after injury (mg/dL; median and interquartile range): ASO 2.5mg/kg: 1.9 (1.3; 3.2), ASO 25mg/kg: 2.8 (0.7; 5.0), mismatch oligonucleotide (MM) 25mg/kg: 5.7 (5,0; 5.8), saline: 4.4 (3.5; 5.8) (P = 0.016, analysis of variance). Blinded semiquantitative histologic evaluation of renal biopsies showed better preserved morphology in both ASO groups than saline- and MM-treated kidneys (median and interquartile range of overall injury scores): ASO both concentrations 1 (1, 1), saline 3 (3, 3) and MM 3 (3, 3) (P< 0.001, analysis of variance). ASO facilitated cell proliferation, metabolism, and angiogenesis on a genome-wide level. ASO when applied in normothermic kidney machine perfusion reduced renal miR-182 expression by more than two magnitudes. In summary, we showed that in vivo inhibition of miR-182 by ASO improved kidney function and morphology after AKI. This technique may be applicable to reduce the high rate of AKI in the human renal transplantation setting.
authors.affiliation: Department of Nephrology and Dialysis, Medical University Vienna, Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Wilflingseder
authors.affiliation: Department of Nephrology and Dialysis, Medical University Vienna, Vienna, Austria.
authors.forename: Kíra
authors.initials: K
authors.lastname: Jelencsics
authors.affiliation: Department of Biomedical Research, Medical University Vienna, Vienna, Austria.
authors.forename: Helga
authors.initials: H
authors.lastname: Bergmeister
authors.affiliation: Department of Nephrology and Dialysis, Medical University Vienna, Vienna, Austria.
authors.forename: Judith
authors.initials: J
authors.lastname: Sunzenauer
authors.affiliation: Department of Pathology, Medical University Vienna, Vienna, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Regele
authors.affiliation: Department of Nephrology and Dialysis, Medical University Vienna, Vienna, Austria.
authors.forename: Farsad
authors.initials: F
authors.lastname: Eskandary
authors.affiliation: Department of Nephrology and Dialysis, Medical University Vienna, Vienna, Austria.
authors.forename: Roman
authors.initials: R
authors.lastname: Reindl-Schwaighofer
authors.affiliation: Department of Nephrology and Dialysis, Medical University Vienna, Vienna, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kainz
authors.affiliation: Department of Nephrology and Dialysis, Medical University Vienna, Vienna, Austria. Electronic address: rainer.oberbauer@meduniwien.ac.at.
authors.forename: Rainer
authors.initials: R
authors.lastname: Oberbauer
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D001706:Biopsy; D002478:Cells, Cultured; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007511:Ischemia / Q000235:genetics* / Q000473:pathology; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000235:genetics / Q000473:pathology; D015203:Reproducibility of Results; D034421:Sus scrofa
chemical_list: C577631:MIRN182 microRNA, rat; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense