Effects of Stimulation of Soluble Guanylate Cyclase on Diabetic Nephropathy in Diabetic eNOS Knockout Mice on Top of Angiotensin II Receptor Blockade 英文参考文献.docVIP

EffectsofStimulationofSolubleGuanylateCyclaseon DiabeticNephropathyinDiabeticeNOSKnockoutMice onTopofAngiotensinIIReceptorBlockade InaM.Ott1,2.,MarkusL.Alter2,3.,KarolinevonWebsky1,2,AxelKretschmer4,OlegTsuprykov1,2, YuliyaSharkovska2,KatharinaKrause-Relle1,2,JensRaila1,AndreaHenze1,Johannes-PeterStasch4,5, BertholdHocher1,2 * 1InstituteforNutritionalScience,UniversityofPotsdam,Potsdam,Germany,2CenterforCardiovascularResearch,Charite′ CampusMitte,Berlin,Germany,3Department ofNephrology,Charite′ CampusBenjaminFranklin,Berlin,Germany,4BayerHealthCareAG,Wuppertal,Germany,5InstituteofPharmacy,UniversityofHalle-Wittenberg, Halle(Saale),Germany Abstract The prevalence of diabetes mellitus and its complications, such as diabetic nephropathy (DN), is rising worldwide and prevention and treatment are therefore becoming increasingly important. Therapy of DN is particularly important for patientswhodonotadequatelyrespondtoangiotensinreceptorblocker(ARB)treatment.Novelapproachesincludethe stimulationofsolubleguanylatecyclase(sGC)asitisreportedtohavebeneficialeffectsoncardiacandrenaldamage.We aimedtoinvestigatetheeffectsofthesGCstimulatorriociguatandARBtelmisartanonkidneyfunctionandstructureina hypertensive model of diabetic nephropathy. Seventy-six diabetic male eNOS knockout C57BL/6J mice were randomly divided after having received streptozotocin: telmisartan (1mg/kg/d), riociguat (3mg/kg/d), riociguat+telmisartan (3+1mg/kg/d),andvehicle.Fourteenmicewereusedasnon-diabeticcontrols.Treatmentdurationwas11weeks. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan insignificantly reduced blood pressure by 5.9mmHgcomparedwithdiabeticcontrols(111.262.3mmHgvs.117.162.2mmHg;p=0.071).Treatmentwithriociguat bothaloneandincombinationwithtelmisartanledtoasignificantreductionofbloodpressuretowardsdiabeticvehicle (105.262.5mmHg and 105.063.2mmHg, respectively, vs. 117.162.2mmHg). Combined treatment also significantly decreased albuminuria c