@misc{HoffmannKretschmerLawrenzetal.2015,
  author    = {Hoffmann, Linda Sarah and Kretschmer, Axel and Lawrenz, Bettina and Hocher, Berthold and Stasch, Johannes-Peter},
  title     = {Chronic activation of heme free Guanylate Cyclase leads to renal protection in Dahl salt-sensitive rats},
  series = {Postprints der Universit{\"a}t Potsdam : Mathematisch naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam : Mathematisch naturwissenschaftliche Reihe},
  number    = {489},
  issn      = {1866-8372},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-408088},
  pages     = {17},
  year      = {2015},
  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 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.},
  language  = {en}
}
@article{TsuprykovChaykovskaKretschmeretal.2015,
  author    = {Tsuprykov, Oleg and Chaykovska, Lyubov and Kretschmer, Axel and Stasch, Johannes-Peter and Pfab, Thiemo and Krause-Relle, Katharina and Reichetzeder, Christoph and Kalk, Philipp and Adamski, Jerzy and Hocher, Berthold},
  title     = {Endothelin-1 overexpression improves renal function in eNOS knockout mice},
  series = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology},
  volume    = {37},
  journal   = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology},
  number    = {4},
  publisher = {Karger},
  address   = {Basel},
  issn      = {1015-8987},
  doi       = {10.1159/000438516},
  pages     = {1474 -- 1490},
  year      = {2015},
  abstract  = {Background/Aims: To investigate the renal phenotype under conditions of an activated renal ET-1 system in the status of nitric oxide deficiency, we compared kidney function and morphology in wild-type, ET-1 transgenic (ET+/+), endothelial nitric oxide synthase knockout (eNOS-/-) and ET+/+eNOS-/- mice. Methods: We assessed blood pressure, parameters of renal morphology, plasma cystatin C, urinary protein excretion, expression of genes associated with glomerular filtration barrier and tissue remodeling, and plasma metabolites using metabolomics. Results: eNOS-/- and ET+/+eNOS-/- mice developed hypertension. Osteopontin, albumin and protein excretion were increased in eNOS-/- and restored in ET+/+eNOS-/- animals. All genetically modified mice developed renal interstitial fibrosis and glomerulosclerosis. Genes involved in tissue remodeling (serpinel, TIMP1, Collal, CCL2) were up-regulated in eNOS-/-, but not in ET+/+eNOS-/- mice. Plasma levels of free carnitine and acylcarnitines, amino acids, diacyl phosphatidylcholines, lysophosphatidylcholines and hexoses were descreased in eNOS-/- and were in the normal range in ET+/+eNOS-/- mice. Conclusion: eNOS-/- mice developed renal dysfunction, which was partially rescued by ET-1 overexpression in eNOS-/- mice. The metabolomics results suggest that ET-1 overexpression on top of eNOS knockout is associated with a functional recovery of mitochondria (rescue effect in 13-oxidation of fatty acids) and an increase in antioxidative properties (normalization of monounsaturated fatty acids levels). (C) 2015 The Author(s) Published by S. Karger AG, Basel},
  language  = {en}
}
@article{StaschSchlossmannHocher2015,
  author    = {Stasch, Johannes-Peter and Schlossmann, Jens and Hocher, Berthold},
  title     = {Renal effects of soluble guanylate cyclase stimulators and activators: A review of the preclinical evidence},
  series = {Current opinion in pharmacology},
  volume    = {21},
  journal   = {Current opinion in pharmacology},
  publisher = {Elsevier},
  address   = {Oxford},
  issn      = {1471-4892},
  doi       = {10.1016/j.coph.2014.12.014},
  pages     = {95 -- 104},
  year      = {2015},
  abstract  = {Direct stimulation of soluble guanylate cyclase (sGC) is emerging as a potential new approach for the treatment of renal disorders. sGC catalyzes the formation of cyclic guanosine monophosphate (cGMP), deficiency of which is implicated in the pathogenesis of chronic kidney disease (CKD). Therefore, new classes of drugs sGC stimulators and activators are being investigated in preclinical models under conditions where nitric oxide is deficient. In preclinical models with different etiologies of CKD, the sGC stimulators BAY 41-2272, BAY 41-8543, BAY 60-4552, riociguat and vericiguat and the sGC activators cinaciguat, ataciguat, BI 703704 and GSK2181236A have shown consistently renoprotective effects. Clinical trials are required to confirm these findings in humans, and to ascertain whether these agents could provide a future alternative to guideline-recommended treatments.},
  language  = {en}
}