TY  - GEN
A1  - Hoffmann, Linda Sarah
A1  - Kretschmer, Axel
A1  - Lawrenz, Bettina
A1  - Hocher, Berthold
A1  - Stasch, Johannes-Peter
T1  - Chronic activation of heme free Guanylate Cyclase leads to renal protection in Dahl salt-sensitive rats
T2  - Postprints der Universität Potsdam : Mathematisch naturwissenschaftliche Reihe
N2  - The nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine monophasphate (cGMP)-signalling pathway is impaired under oxidative stress conditions due to oxidation and subsequent loss of the prosthetic sGC heme group as observed in particular in chronic renal failure. Thus, the pool of heme free sGC is increased under pathological conditions. sGC activators such as cinaciguat selectively activate the heme free form of sGC and target the disease associated enzyme. In this study, a therapeutic effect of long-term activation of heme free sGC by the sGC activator cinaciguat was investigated in an experimental model of salt-sensitive hypertension, a condition that is associated with increased oxidative stress, heme loss from sGC and development of chronic renal failure. For that purpose Dahl/ss rats, which develop severe hypertension upon high salt intake, were fed a high salt diet (8% NaCl) containing either placebo or cinaciguat for 21 weeks. Cinaciguat markedly improved survival and ameliorated the salt-induced increase in blood pressure upon treatment with cinaciguat compared to placebo. Renal function was significantly improved in the cinaciguat group compared to the placebo group as indicated by a significantly improved glomerular filtration rate and reduced urinary protein excretion. This was due to anti-fibrotic and antiinflammatory effects of the cinaciguat treatment. Taken together, this is the first study showing that long-term activation of heme free sGC leads to renal protection in an experimental model of hypertension and chronic kidney disease. These results underline the promising potential of cinaciguat to treat renal diseases by targeting the disease associated heme free form of sGC.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 489 
KW  - signal-transduction system
KW  - nitric-oxide
KW  - oxidative stress
KW  - independent activation
KW  - endothelial dysfunction
KW  - pulmonary-hypertension
KW  - cardiovascular-disease
KW  - therapeutic target
KW  - heart-failure
KW  - cyclic-GMP
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-408088
SN  - 1866-8372
IS  - 489
ER  - 
TY  - JOUR
A1  - Benina, Maria
A1  - Ribeiro, Dimas Mendes
A1  - Gechev, Tsanko S.
A1  - Müller-Röber, Bernd
A1  - Schippers, Jos H. M.
T1  - A cell type-specific view on the translation of mRNAs from ROS-responsive genes upon paraquat treatment of Arabidopsis thaliana leaves
JF  - Plant, cell & environment : cell physiology, whole-plant physiology, community physiology
N2  - Oxidative stress causes dramatic changes in the expression levels of many genes. The formation of a functional protein through successful mRNA translation is central to a coordinated cellular response. To what extent the response towards reactive oxygen species (ROS) is regulated at the translational level is poorly understood. Here we analysed leaf- and tissue-specific translatomes using a set of transgenic Arabidopsis thaliana lines expressing a FLAG-tagged ribosomal protein to immunopurify polysome-bound mRNAs before and after oxidative stress. We determined transcript levels of 171 ROS-responsive genes upon paraquat treatment, which causes formation of superoxide radicals, at the whole-organ level. Furthermore, the translation of mRNAs was determined for five cell types: mesophyll, bundle sheath, phloem companion, epidermal and guard cells. Mesophyll and bundle sheath cells showed the strongest response to paraquat treatment. Interestingly, several ROS-responsive transcription factors displayed cell type-specific translation patterns, while others were translated in all cell types. In part, cell type-specific translation could be explained by the length of the 5-untranslated region (5-UTR) and the presence of upstream open reading frames (uORFs). Our analysis reveals insights into the translational regulation of ROS-responsive genes, which is important to understanding cell-specific responses and functions during oxidative stress.
 The study illustrates the response of different Arabidopsis thaliana leaf cells and tissues to oxidative stress at the translational level, an aspect of reactive oxygen species (ROS) biology that has been little studied in the past. Our data reveal insights into how translational regulation of ROS-responsive genes is fine-tuned at the cellular level, a phenomenon contributing to the integrated physiological response of leaves to stresses involving changes in ROS levels.
KW  - Arabidopsis
KW  - gene regulation
KW  - oxidative stress
KW  - tissue-specific
KW  - translation
Y1  - 2015
U6  - https://doi.org/10.1111/pce.12355
SN  - 0140-7791
SN  - 1365-3040
VL  - 38
IS  - 2
SP  - 349
EP  - 363
PB  - Wiley-Blackwell
CY  - Hoboken
ER  -