title: Direct renin inhibition prevents cardiac dysfunction in a diabetic mouse model: comparison with an angiotensin receptor antagonist and angiotensin-converting enzyme inhibitor.
abstract: Hyperglycaemia up-regulates intracellular AngII (angiotensin II) production in cardiac myocytes, effects of which are blocked more effectively by renin inhibition than ARBs (angiotensin receptor blockers) or ACEis (angiotensin-converting enzyme inhibitors). In the present study, we determined whether renin inhibition is more effective at preventing diabetic cardiomyopathy than an ARB or ACEi. Diabetes was induced in adult mice for 10 weeks by STZ (streptozotocin). Diabetic mice were treated with insulin, aliskiren (a renin inhibitor), benazeprilat (an ACEi) or valsartan (an ARB) via subcutaneous mini-pumps. Significant impairment in diastolic and systolic cardiac functions was observed in diabetic mice, which was completely prevented by all three RAS (renin-angiotensin system) inhibitors. Hyperglycaemia significantly increased cardiac oxidative stress and circulating inflammatory cytokines, which were blocked by aliskiren and benazeprilat, whereas valsartan was partially effective. Diabetes increased cardiac PRR (prorenin receptor) expression and nuclear translocation of PLZF (promyelocytic zinc finger protein), which was completely prevented by aliskiren and valsartan, and partially by benazeprilat. Renin inhibition provided similar protection of cardiac function to ARBs and ACEis. Activation of PLZF by PRR represented a novel mechanism in diabetic cardiomyopathy. Differential effects of the three agents on oxidative stress, cytokines and PRR expression suggested subtle differences in their mechanisms of action.
authors.affiliation: Division of Molecular Cardiology, Department of Medicine, Texas A&M Health Science Center, College of Medicine; Scott and White; Central Texas Veterans Health Care System, Temple, TX 76504, USA.
authors.forename: Candice M
authors.initials: CM
authors.lastname: Thomas
authors.forename: Qian Chen
authors.initials: QC
authors.lastname: Yong
authors.forename: Rachid
authors.initials: R
authors.lastname: Seqqat
authors.forename: Niketa
authors.initials: N
authors.lastname: Chandel
authors.forename: David L
authors.initials: DL
authors.lastname: Feldman
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Baker
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000577:Amides / Q000008:administration & dosage; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D005650:Fumarates / Q000008:administration & dosage; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D012083:Renin / Q000378:metabolism; D013777:Tetrazoles / Q000008:administration & dosage; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068756:Valsartan; D000093342:Prorenin Receptor; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D005650:Fumarates; D011956:Receptors, Cell Surface; D012083:Renin; D013777:Tetrazoles; D014633:Valine; D000068756:Valsartan; D000093342:Prorenin Receptor; D000092502:Renin Inhibitors; C446481:aliskiren; C052133:benazeprilat