AIMS: Although ACE inhibitors slow progression of diabetic renal disease, the mortality and morbidity is still high. As other hormonal factors are involved, inhibition of vasopeptidases could further reduce progression. We studied dual inhibition of angiotensin converting enzyme and neutral endopeptidase in a model of progressive diabetic renal injury. The major endpoints were reductions in systemic blood pressure, albuminuria and renal structural injury. METHODS: Diabetic spontaneously hypertensive rats were treated with the ACE inhibitor perindopril (mg.kg(-1).day(-1)) or the vasopeptidase inhibitor omapatrilat at doses of 10 (oma10) and 40 (oma40) mg.kg(-1).day(-1) for 32 weeks. In vivo ACE and NEP inhibition was quantitated by in vitro autoradiography. Renal structural injury was assessed by measurement of the glomerulosclerotic (GS) index and tubulointerstitial area (TI). The expression of transforming growth factor beta, beta-inducible gene-h3 and nephrin were also quantitated. RESULTS: Despite a similar reduction in blood pressure by perindopril and oma10, greater attenuation of albuminuria was afforded by oma10, with a complete amelioration observed with oma40. Oma40 lead to a 33% reduction in renal NEP binding and this was associated with less albuminuria and prevention of GS, TI area and overexpression of TGFbeta and betaig-h3. Diabetes-associated reduction in nephrin expression was restored by both drugs. CONCLUSION/ INTERPRETATION: These findings suggest that other vasoactive mechanisms in addition to angiotensin II are important in the prevention of diabetic nephropathy, and that vasopeptidase inhibition might confer an advantage over blockade of the RAS alone in the treatment of diabetic renal disease.
AIMS: Although ACE inhibitors slow progression of diabetic renal disease, the mortality and morbidity is still high. As other hormonal factors are involved, inhibition of vasopeptidases could further reduce progression. We studied dual inhibition of angiotensin converting enzyme and neutral endopeptidase in a model of progressive diabetic renal injury. The major endpoints were reductions in systemic blood pressure, albuminuria and renal structural injury. METHODS:Diabetic spontaneously hypertensiverats were treated with the ACE inhibitor perindopril (mg.kg(-1).day(-1)) or the vasopeptidase inhibitor omapatrilat at doses of 10 (oma10) and 40 (oma40) mg.kg(-1).day(-1) for 32 weeks. In vivo ACE and NEP inhibition was quantitated by in vitro autoradiography. Renal structural injury was assessed by measurement of the glomerulosclerotic (GS) index and tubulointerstitial area (TI). The expression of transforming growth factor beta, beta-inducible gene-h3 and nephrin were also quantitated. RESULTS: Despite a similar reduction in blood pressure by perindopril and oma10, greater attenuation of albuminuria was afforded by oma10, with a complete amelioration observed with oma40. Oma40 lead to a 33% reduction in renal NEP binding and this was associated with less albuminuria and prevention of GS, TI area and overexpression of TGFbeta and betaig-h3. Diabetes-associated reduction in nephrin expression was restored by both drugs. CONCLUSION/ INTERPRETATION: These findings suggest that other vasoactive mechanisms in addition to angiotensin II are important in the prevention of diabetic nephropathy, and that vasopeptidase inhibition might confer an advantage over blockade of the RAS alone in the treatment of diabetic renal disease.
Authors: Christine A Houlihan; Terri J Allen; Amynta L Baxter; Sianna Panangiotopoulos; David J Casley; Mark E Cooper; George Jerums Journal: Diabetes Care Date: 2002-04 Impact factor: 19.112
Authors: J R Rumble; M E Cooper; T Soulis; A Cox; L Wu; S Youssef; M Jasik; G Jerums; R E Gilbert Journal: J Clin Invest Date: 1997-03-01 Impact factor: 14.808
Authors: F N Ziyadeh; B B Hoffman; D C Han; M C Iglesias-De La Cruz; S W Hong; M Isono; S Chen; T A McGowan; K Sharma Journal: Proc Natl Acad Sci U S A Date: 2000-07-05 Impact factor: 11.205
Authors: A Remuzzi; N Perico; C S Amuchastegui; B Malanchini; M Mazerska; C Battaglia; T Bertani; G Remuzzi Journal: J Am Soc Nephrol Date: 1993-07 Impact factor: 10.121
Authors: M C Fournié-Zaluski; W Gonzalez; S Turcaud; I Pham; B P Roques; J B Michel Journal: Proc Natl Acad Sci U S A Date: 1994-04-26 Impact factor: 11.205
Authors: C Wihler; S Schäfer; K Schmid; E K Deemer; G Münch; M Bleich; A E Busch; T Dingermann; V Somoza; J W Baynes; J Huber Journal: Diabetologia Date: 2005-07-12 Impact factor: 10.122
Authors: Stefan Schäfer; Hans-Ludwig Schmidts; Markus Bleich; Andreas E Busch; Wolfgang Linz Journal: Br J Pharmacol Date: 2004-08-02 Impact factor: 8.739