SCIENTIFIC REPORts | (2018) 8:3438 | DOI:10.1038/s41598-018-21720-3
Hypoxia-induced long non-coding
RNA Malat1 is dispensable for renal
, Celina Genschel
, Tamas Kaucsar
, Anika Hübner
, Song Rong
, Inga Sörensen-Zender
, George Haddad
, Andreas Kistler
, Harald Seeger
, Danilo Fliser
, Hermann Haller
, Rudolf Wüthrich
, Martin Zörnig
& Johan Lorenzen
Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury (AKI). Non-coding RNAs
are crucially involved in its pathophysiology. We identied hypoxia-induced long non-coding RNA
Malat1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) to be upregulated in renal I/R injury.
We here elucidated the functional role of Malat1 in vitro and its potential contribution to kidney injury
in vivo. Malat1 was upregulated in kidney biopsies and plasma of patients with AKI, in murine hypoxic
kidney tissue as well as in cultured and ex vivo sorted hypoxic endothelial cells and tubular epithelial
cells. Malat1 was transcriptionally activated by hypoxia-inducible factor 1-α. In vitro, Malat1 inhibition
reduced proliferation and the number of endothelial cells in the S-phase of the cell cycle. In vivo, Malat1
knockout and wildtype mice showed similar degrees of outer medullary tubular epithelial injury,
proliferation, capillary rarefaction, inammation and brosis, survival and kidney function. Small-RNA
sequencing and whole genome expression analysis revealed only minor changes between ischemic
Malat1 knockout and wildtype mice. Contrary to previous studies, which suggested a prominent role
of Malat1 in the induction of disease, we did not conrm an in vivo role of Malat1 concerning renal I/R-
Ischemia-reperfusion (I/R) injury of the kidney is a major cause of acute kidney injury. Due to its high morbidity
and mortality it represents a major socioeconomic health problem
. A variety of injurious insults in native kid-
neys may promote its development (e.g. during cardiac surgery). In addition, it is an unavoidable phenomenon
during the kidney transplantation procedure
. We and others have previously shown that non-coding RNAs may
contribute to the induction or resolution of this process
e number of RNA transcripts without protein-coding potential exceeds 98% of the human genome
arbitration these non-coding RNAs (ncRNAs) are divided into long ncRNAs (lncRNAs, ≥200 nucleotides) and
small ncRNAs (≤200 nucleotides). Small RNAs such as microRNAs have previously been well characterized.
Similar to microRNAs, lncRNAs have recently been shown to regulate gene expression
. e study of the function
of lncRNAs is still in its infancy and currently a matter of intense research initiatives. LncRNAs may interact with
all components of the cellular machinery, including protein, DNA and RNA
. e lncRNA metastasis-associated
lung adenocarcinoma transcript 1 (Malat1) (alternative nomenclature: Nuclear enriched abundant transcript 2
(Neat2)) is nuclear enriched and controls alternative splicing by interacting with serine/arginine splicing factors
in nuclear speckle domains
. It has been shown to regulate hyperglycemia induced inammatory processes in
. It also regulates cell motility via the transcriptional and/or post-transcriptional regulation of
. It has been shown to regulate endothelial cell function and vessel growth
. In addition,
Department of Nephrology, University Hospital, Zürich, Switzerland.
Institute of Molecular and Translational
Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.
Department of Nephrology,
Hannover Medical School, Hannover, Germany.
National Heart and Lung Institute, Imperial College London, London,
Semmelweis University, Budapest, Hungary.
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental
Therapy, Frankfurt, Germany.
Department of Nephrology, Städtisches Klinikum Braunschweig GmbH, Braunschweig,
Saarland University Medical Centre, Homburg/Saar, Germany.
Department of Internal Medicine, Cantonal
Hospital Frauenfeld, Frauenfeld, Switzerland.
Excellence Cluster REBIRTH, Hannover Medical School, Hannover,
Germany. Correspondence and requests for materials should be addressed to J.L. (email: Johan.Lorenzen@usz.ch)
Received: 11 October 2017
Accepted: 9 February 2018
Published: xx xx xxxx