title: A Soluble Guanylate Cyclase Activator Inhibits the Progression of Diabetic Nephropathy in the ZSF1 Rat.
abstract: 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.
authors.affiliation: Departments of Cardiometabolic Diseases Research (C.M.B.-K., P.C.H., H.C., K.A.L., H.S.Q., H.C., H.W., X.Z., R.M.F., J.G.R., S.S.P.) and Small Molecule Discovery Research (K.G.-B., T.B., D.W., C.S.), Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut carine.boustany@boehringer-ingelheim.com.
authors.forename: Carine M
authors.initials: CM
authors.lastname: Boustany-Kari
authors.affiliation: Departments of Cardiometabolic Diseases Research (C.M.B.-K., P.C.H., H.C., K.A.L., H.S.Q., H.C., H.W., X.Z., R.M.F., J.G.R., S.S.P.) and Small Molecule Discovery Research (K.G.-B., T.B., D.W., C.S.), Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Harrison
authors.affiliation: Departments of Cardiometabolic Diseases Research (C.M.B.-K., P.C.H., H.C., K.A.L., H.S.Q., H.C., H.W., X.Z., R.M.F., J.G.R., S.S.P.) and Small Molecule Discovery Research (K.G.-B., T.B., D.W., C.S.), Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
authors.forename: Hongxing
authors.initials: H
authors.lastname: Chen
authors.affiliation: Departments of Cardiometabolic Diseases Research (C.M.B.-K., P.C.H., H.C., K.A.L., H.S.Q., H.C., H.W., X.Z., R.M.F., J.G.R., S.S.P.) and Small Molecule Discovery Research (K.G.-B., T.B., D.W., C.S.), Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Lincoln
authors.affiliation: Departments of Cardiometabolic Diseases Research (C.M.B.-K., P.C.H., H.C., K.A.L., H.S.Q., H.C., H.W., X.Z., R.M.F., J.G.R., S.S.P.) and Small Molecule Discovery Research (K.G.-B., T.B., D.W., C.S.), Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
authors.forename: Hu Sheng
authors.initials: HS
authors.lastname: Qian
authors.affiliation: Departments of Cardiometabolic Diseases Research (C.M.B.-K., P.C.H., H.C., K.A.L., H.S.Q., H.C., H.W., X.Z., R.M.F., J.G.R., S.S.P.) and Small Molecule Discovery Research (K.G.-B., T.B., D.W., C.S.), Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
authors.forename: Holly
authors.initials: H
authors.lastname: Clifford
authors.affiliation: Departments of Cardiometabolic Diseases Research (C.M.B.-K., P.C.H., H.C., K.A.L., H.S.Q., H.C., H.W., X.Z., R.M.F., J.G.R., S.S.P.) and Small Molecule Discovery Research (K.G.-B., T.B., D.W., C.S.), Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Departments of Cardiometabolic Diseases Research (C.M.B.-K., P.C.H., H.C., K.A.L., H.S.Q., H.C., H.W., X.Z., R.M.F., J.G.R., S.S.P.) and Small Molecule Discovery Research (K.G.-B., T.B., D.W., C.S.), Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Departments of Cardiometabolic Diseases Research (C.M.B.-K., P.C.H., H.C., K.A.L., H.S.Q., H.C., H.W., X.Z., R.M.F., J.G.R., S.S.P.) and Small Molecule Discovery Research (K.G.-B., T.B., D.W., C.S.), Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
authors.forename: Kristina
authors.initials: K
authors.lastname: Gueneva-Boucheva
authors.affiliation: Departments of Cardiometabolic Diseases Research (C.M.B.-K., P.C.H., H.C., K.A.L., H.S.Q., H.C., H.W., X.Z., R.M.F., J.G.R., S.S.P.) and Small Molecule Discovery Research (K.G.-B., T.B., D.W., C.S.), Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
authors.forename: Todd
authors.initials: T
authors.lastname: Bosanac
authors.affiliation: Departments of Cardiometabolic Diseases Research (C.M.B.-K., P.C.H., H.C., K.A.L., H.S.Q., H.C., H.W., X.Z., R.M.F., J.G.R., S.S.P.) and Small Molecule Discovery Research (K.G.-B., T.B., D.W., C.S.), Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
authors.forename: Diane
authors.initials: D
authors.lastname: Wong
authors.affiliation: Departments of Cardiometabolic Diseases Research (C.M.B.-K., P.C.H., H.C., K.A.L., H.S.Q., H.C., H.W., X.Z., R.M.F., J.G.R., S.S.P.) and Small Molecule Discovery Research (K.G.-B., T.B., D.W., C.S.), Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Fryer
authors.affiliation: Departments of Cardiometabolic Diseases Research (C.M.B.-K., P.C.H., H.C., K.A.L., H.S.Q., H.C., H.W., X.Z., R.M.F., J.G.R., S.S.P.) and Small Molecule Discovery Research (K.G.-B., T.B., D.W., C.S.), Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
authors.forename: Jeremy G
authors.initials: JG
authors.lastname: Richman
authors.affiliation: Departments of Cardiometabolic Diseases Research (C.M.B.-K., P.C.H., H.C., K.A.L., H.S.Q., H.C., H.W., X.Z., R.M.F., J.G.R., S.S.P.) and Small Molecule Discovery Research (K.G.-B., T.B., D.W., C.S.), Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
authors.forename: Chris
authors.initials: C
authors.lastname: Sarko
authors.affiliation: Departments of Cardiometabolic Diseases Research (C.M.B.-K., P.C.H., H.C., K.A.L., H.S.Q., H.C., H.W., X.Z., R.M.F., J.G.R., S.S.P.) and Small Molecule Discovery Research (K.G.-B., T.B., D.W., C.S.), Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Pullen
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000201:enzymology*; D018450:Disease Progression; D015773:Enalaprilat / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006162:Guanylate Cyclase / Q000378:metabolism*; D008297:Male; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase
chemical_list: D020536:Enzyme Activators; D018160:Receptors, Cytoplasmic and Nuclear; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D015773:Enalaprilat