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Research ArticleDrug Discovery and Translational Medicine

A Soluble Guanylate Cyclase Activator Inhibits the Progression of Diabetic Nephropathy in the ZSF1 rat

Carine M. Boustany-Kari, Paul C. Harrison, Xongxing Chen, Kathleen Lincoln, Hu Sheng Qian, Holly Clifford, Hong Wang, Xiaomei Zhang, Kristina Gueneva-Boucheva, Todd Bosanac, Diane Wong, Ryan M. Fryer, Jeremy G. Richman, Chris Sarko and Steven M Pullen
Journal of Pharmacology and Experimental Therapeutics January 4, 2016, jpet.115.230706; DOI: https://doi.org/10.1124/jpet.115.230706
Carine M. Boustany-Kari
Boehringer Ingelheim Pharmaceuticals, Inc
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Paul C. Harrison
Boehringer Ingelheim Pharmaceuticals, Inc
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Xongxing Chen
Boehringer Ingelheim Pharmaceuticals, Inc
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Kathleen Lincoln
Boehringer Ingelheim Pharmaceuticals, Inc
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Hu Sheng Qian
Boehringer Ingelheim Pharmaceuticals, Inc
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Holly Clifford
Boehringer Ingelheim Pharmaceuticals, Inc
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Hong Wang
Boehringer Ingelheim Pharmaceuticals, Inc
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Xiaomei Zhang
Boehringer Ingelheim Pharmaceuticals, Inc
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Kristina Gueneva-Boucheva
Boehringer Ingelheim Pharmaceuticals, Inc
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Todd Bosanac
Boehringer Ingelheim Pharmaceuticals, Inc
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Diane Wong
Boehringer Ingelheim Pharmaceuticals, Inc
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Ryan M. Fryer
Boehringer Ingelheim Pharmaceuticals, Inc
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Jeremy G. Richman
Boehringer Ingelheim Pharmaceuticals, Inc
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Chris Sarko
Boehringer Ingelheim Pharmaceuticals, Inc
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Steven M Pullen
Boehringer Ingelheim Pharmaceuticals, Inc
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Abstract

Therapies which restore renal cyclic GMP (cGMP) levels are hypothesized to slow the progression of diabetic nephropathy. We investigated the effect of BI 703704, a soluble guanylate cyclase (sGC) activator, on disease progression in obese ZSF1 rats. BI 703704 was administered at doses of 0.3, 1, 3 and 10 mg/kg/day to male ZSF1 rats for 15 weeks, during which mean arterial pressure (MAP), heart rate (HR), and urinary protein excretion (UPE) were determined. Histological assessment of glomerular and interstitial lesions was also performed. Renal cGMP levels were quantified as an indicator of target modulation. BI 703704 resulted in sGC activation as evidenced by dose-dependent increases in renal cGMP levels. After 15 weeks of treatment, sGC activation resulted in dose-dependent decreases in UPE (from 463±58 mg/day in vehicle controls to 328±55, 348±23, 283±45 and 108±23 mg/day in BI 703704 treated rats at 0.3, 1, 3 and 10 mg/kg, respectively). These effects were accompanied by a significant reduction in the incidence of glomerulosclerosis and interstitial lesions. Decreases in MAP and increases in HR were only observed at the high dose of BI 703704. These results are the first demonstration of renal protection with sGC activation in a nephropathy model induced by type 2 diabetes. Importantly, beneficial effects were observed at doses that did not significantly alter MAP and HR.

  • cGMP
  • drug efficacy
  • kidney
  • nitric oxide
  • renal failure
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleDrug Discovery and Translational Medicine

A Soluble Guanylate Cyclase Activator Inhibits the Progression of Diabetic Nephropathy in the ZSF1 rat

Carine M. Boustany-Kari, Paul C. Harrison, Xongxing Chen, Kathleen Lincoln, Hu Sheng Qian, Holly Clifford, Hong Wang, Xiaomei Zhang, Kristina Gueneva-Boucheva, Todd Bosanac, Diane Wong, Ryan M. Fryer, Jeremy G. Richman, Chris Sarko and Steven M Pullen
Journal of Pharmacology and Experimental Therapeutics January 4, 2016, jpet.115.230706; DOI: https://doi.org/10.1124/jpet.115.230706

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Research ArticleDrug Discovery and Translational Medicine

A Soluble Guanylate Cyclase Activator Inhibits the Progression of Diabetic Nephropathy in the ZSF1 rat

Carine M. Boustany-Kari, Paul C. Harrison, Xongxing Chen, Kathleen Lincoln, Hu Sheng Qian, Holly Clifford, Hong Wang, Xiaomei Zhang, Kristina Gueneva-Boucheva, Todd Bosanac, Diane Wong, Ryan M. Fryer, Jeremy G. Richman, Chris Sarko and Steven M Pullen
Journal of Pharmacology and Experimental Therapeutics January 4, 2016, jpet.115.230706; DOI: https://doi.org/10.1124/jpet.115.230706
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