PT - JOURNAL ARTICLE AU - Carine M. Boustany-Kari AU - Paul C. Harrison AU - Hongxing Chen AU - Kathleen A. Lincoln AU - Hu Sheng Qian AU - Holly Clifford AU - Hong Wang AU - Xiaomei Zhang AU - Kristina Gueneva-Boucheva AU - Todd Bosanac AU - Diane Wong AU - Ryan M. Fryer AU - Jeremy G. Richman AU - Chris Sarko AU - Steven S. Pullen TI - A Soluble Guanylate Cyclase Activator Inhibits the Progression of Diabetic Nephropathy in the ZSF1 Rat AID - 10.1124/jpet.115.230706 DP - 2016 Mar 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 712--719 VI - 356 IP - 3 4099 - http://jpet.aspetjournals.org/content/356/3/712.short 4100 - http://jpet.aspetjournals.org/content/356/3/712.full SO - J Pharmacol Exp Ther2016 Mar 01; 356 AB - Therapies that restore renal 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/d to male ZSF1 rats for 15 weeks, during which mean arterial pressure (MAP), heart rate (HR), and urinary protein excretion (UPE) were determined. Histologic 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/d in vehicle controls to 328 ± 55, 348 ± 23, 283 ± 45, and 108 ± 23 mg/d 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.