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
UR  - https://publishup.uni-potsdam.de/frontdoor/index/index/docId/40808
UR  - https://nbn-resolving.org/urn:nbn:de:kobv:517-opus4-408088
SN  - 1866-8372
IS  - 489
ER  -