N-octanoyl-Dopamine Is an Agonist at the Capsaicin Receptor TRPV1 and Mitigates Is Chemia-Induced Acute Kidney Injury in Rat

Charalambos Tsagogiorgas,Peter Schnuelle,Michael O Schneider,Rüdiger Waldherr,Maximilia Hottenrott,Simone Hoeger,Rolf-Detlef Treede,Bernhard K Krämer,Sonja Theisinger,Bastian Theisinger,Manfred Thiel,Wolfgang Greffrath,Johannes Wedel,Benito A Yard,Uta Binzen,Emmanuel A Burdmann

doi:10.1371/journal.pone.0043525

Charalambos Tsagogiorgas, Peter Schnuelle + Show 14 more

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https://doi.org/10.1371/journal.pone.0043525

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Abstract

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.

Highlights

Acute kidney injury (AKI) is common in critically ill patients and is associated with a substantially increased morbidity and mortality [1,2]
At higher magnification PGP9.5 expressing peripheral nerve fibers localized between renal tubuli and some of the tubuli showed a positive staining for the capsaicin receptor TRPV1 (Fig. 2B, middle panels)
Peripheral nerve fibers originate from the soma of dorsal root ganglion neurons (DRG), a tissue known to extensively express TRPV1 [37,38]

Summary

Introduction

Acute kidney injury (AKI) is common in critically ill patients and is associated with a substantially increased morbidity and mortality [1,2]. Inflammation is believed to play a major role in the pathophysiology of AKI [5,6]. In AKI, loss of renal function is attributed to severe tubular injury as a consequence of an increased amount of reactive oxygen radicals, leading to apoptosis and necrosis [7,8]. In addition to their passive role in AKI, proximal tubular epithelial cells produce numerous chemokines upon oxidative stress, which further perpetuates ongoing inflammation [9]

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