N-octanoyl-dopamine is an agonist at the capsaicin receptor TRPV1 and mitigates ischemia-induced [corrected] acute kidney injury in rat.
Since stimulation of transient receptor potential channels of the vanilloid receptor subtype 1 (TRPV1) mitigates acute kidney injury (AKI) and endogenous N-acyl dopamine derivatives are able to activate TRPV1, we tested if synthetic N-octanoyl-dopamine (NOD) activates TRPV1 and if it improves AKI. These properties of NOD and its intrinsic anti-inflammatory character were compared with those of dopamine (DA). TRPV1 activation and anti-inflammatory properties of NOD and DA were tested using primary cell cultures in vitro. The influence of NOD and DA on AKI was tested in a prospective, randomized, controlled animal study with 42 inbred male Lewis rats (LEW, RT1), treated intravenously with equimolar concentrations of DA or NOD one hour before the onset of warm ischemia and immediately before clamp release. NOD, but not DA, activates TRPV1 channels in isolated dorsal root ganglion neurons (DRG) that innervate several tissues including kidney. In TNFα stimulated proximal tubular epithelial cells, inhibition of NFκB and subsequent inhibition of VCAM1 expression by NOD was significantly stronger than by DA. NOD improved renal function compared to DA and saline controls. Histology revealed protective effects of NOD on tubular epithelium at day 5 and a reduced number of monocytes in renal tissue of DA and NOD treated rats. Our data demonstrate that NOD but not DA activates TRPV1 and that NOD has superior anti-inflammatory properties in vitro. Although NOD mitigates deterioration in renal function after AKI, further studies are required to assess to what extend this is causally related to TRPV1 activation and/or desensitization.
Department of Anaesthesiology and Intensive Care Medicine, University Medical Centre Mannheim, Medical Faculty Mannheim, Ruprecht Karls University Heidelberg, Mannheim, Germany. charalambos.tsagogiorgas@medma.uni-heidelberg.de
Charalambos
C
Tsagogiorgas
Johannes
J
Wedel
Maximilia
M
Hottenrott
Michael O
MO
Schneider
Uta
U
Binzen
Wolfgang
W
Greffrath
Rolf-Detlef
RD
Treede
Bastian
B
Theisinger
Sonja
S
Theisinger
Rüdiger
R
Waldherr
Bernhard K
BK
Krämer
Manfred
M
Thiel
Peter
P
Schnuelle
Benito A
BA
Yard
Simone
S
Hoeger
D058186:Acute Kidney Injury / Q000188:drug therapy*; D000818:Animals; D015153:Blotting, Western; D004298:Dopamine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D024202:Electrophoretic Mobility Shift Assay; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism; D016133:Polymerase Chain Reaction; D051381:Rats; D050916:TRPV Cation Channels / Q000819:agonists*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
C554838:N-octanoyldopamine; D016328:NF-kappa B; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D019010:Vascular Cell Adhesion Molecule-1; D004298:Dopamine