title: Chronic Activation of Heme Free Guanylate Cyclase Leads to Renal Protection in Dahl Salt-Sensitive Rats.
abstract: 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 anti-inflammatory 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.
authors.affiliation: Pharma Research Centre, Bayer HealthCare, Wuppertal, Germany.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Hoffmann
authors.affiliation: Pharma Research Centre, Bayer HealthCare, Wuppertal, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Kretschmer
authors.affiliation: Pharma Research Centre, Bayer HealthCare, Wuppertal, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Lawrenz
authors.affiliation: Instute of Nutritional Science, University of Potsdam, Potsdam, Germany, and IFLb Laboratoriumsmedizin Berlin GmbH, Berlin, Germany.
authors.forename: Berthold
authors.initials: B
authors.lastname: Hocher
authors.affiliation: Pharma Research Centre, Bayer HealthCare, Wuppertal, Germany.|School of Pharmacy, Martin-Luther-University, Halle an der Saale, Germany.
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000502:physiology; D006162:Guanylate Cyclase / Q000378:metabolism*; D006418:Heme / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006418:Heme; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP