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Tsuprykov, O.* ; Chaykovska, L.* ; Kretschmer, D.* ; Stasch, J.-P.* ; Pfab, T.* ; Krause-Relle, K.* ; Reichetzeder. C.* ; Kalk, P.* ; Adamski, J. ; Hocher, B.*

Endothelin-1 overexpression improves renal function in eNOS knockout mice.

Cell. Physiol. Biochem. 37, 1474-1490 (2015)
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BACKGROUND/AIMS: To investigate the renal phenotype under conditions of an activated renal ET-1 system in the status of nitric oxide deficiency, we compared kidney function and morphology in wild-type, ET-1 transgenic (ET+/+), endothelial nitric oxide synthase knockout (eNOS-/-) and ET+/+eNOS-/- mice. METHODS: We assessed blood pressure, parameters of renal morphology, plasma cystatin C, urinary protein excretion, expression of genes associated with glomerular filtration barrier and tissue remodeling, and plasma metabolites using metabolomics. RESULTS: eNOS-/- and ET+/+eNOS-/- mice developed hypertension. Osteopontin, albumin and protein excretion were increased in eNOS-/- and restored in ET+/+eNOS-/- animals. All genetically modified mice developed renal interstitial fibrosis and glomerulosclerosis. Genes involved in tissue remodeling (serpine1, TIMP1, Col1a1, CCL2) were up-regulated in eNOS-/-, but not in ET+/+eNOS-/- mice. Plasma levels of free carnitine and acylcarnitines, amino acids, diacyl phosphatidylcholines, lysophosphatidylcholines and hexoses were descreased in eNOS-/- and were in the normal range in ET+/+eNOS-/- mice. CONCLUSION: eNOS-/- mice developed renal dysfunction, which was partially rescued by ET-1 overexpression in eNOS-/- mice. The metabolomics results suggest that ET-1 overexpression on top of eNOS knockout is associated with a functional recovery of mitochondria (rescue effect in β-oxidation of fatty acids) and an increase in antioxidative properties (normalization of monounsaturated fatty acids levels).
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Publication type Article: Journal article
Document type Scientific Article
Keywords Chronic Kidney Disease ; Endothelial Nitric Oxide Synthase ; Endothelin ; Mice ; Nitric Oxide
Language english
Publication Year 2015
HGF-reported in Year 2015
ISSN (print) / ISBN 1015-8987
e-ISSN 1421-9778
Quellenangaben Volume: 37, Issue: 4, Pages: 1474-1490 Article Number: , Supplement: ,
Publisher Karger
Reviewing status Peer reviewed
Institute(s) Molekulare Endokrinologie und Metabolismus (MEM)
Institute of Experimental Genetics (IEG)
POF-Topic(s) 30201 - Metabolic Health
90000 - German Center for Diabetes Research
Research field(s) Genetics and Epidemiology
PSP Element(s) G-505600-003
G-501900-061
PubMed ID 26509263
PubMed ID 2650926
Scopus ID 84946781840
Erfassungsdatum 2015-11-04