Inhibition of renin angiotensin system decreases renal protein oxidative damage in diabetic rats.
Renin angiotensin system (RAS) worsens diabetic nephropathy (DN) by increasing oxidative stress. We compared the effect of three different RAS inhibitors: the angiotensin converting enzyme inhibitor Ramipril, the vasopeptidase inhibitor AVE7688 and the angiotensin receptor (AT1) antagonist Losartan on the formation of oxidative and carbonyl stress derived protein modifications in kidney from Zucker obese hyperglycemic rats (ZDFn Gm-fa/fa). Gas chromatography-mass spectrometry was used to measure representative markers of several protein oxidative pathways: direct oxidation [dinitrophenylhydrazine reactive carbonyls (DNP), glutamic (GSA), and aminoadipic (AASA) semialdehydes], mixed glyco- and lipoxidation [N(epsilon)-carboxyethyl-lysine (CEL) and N(epsilon)-(carboxymethyl)-lysine (CML)] and lipoxidation-[N(epsilon)-(malondialdehyde)-lysine-(MDAL)], as well as renal fatty acid composition. Urinary albumin (a marker of DN), DNP, GSA, and MDAL levels, were increased in all obese rats and were dose dependently decreased by AVE7688 whereas Ramipril and Losartan were less efficient. These results show that RAS inhibition improves DN at several levels, independently of its effects on blood pressure and glycemic control, via mechanisms depending of renal oxidative stress.
Portero-Otín
Manuel
M
Department of Experimental Medicine, Faculty of Medicine, University of Lleida-IRBLLEIDA-PCiTAL (Parc Científic Agroalimentari de Lleida), 25008 Lleida, Spain.
Pamplona
Reinald
R
Boada
Jordi
J
Jové
Mariona
M
Gonzalo
Hugo
H
Buleon
Marie
M
Linz
Wolfgang
W
Schäfer
Stefan
S
Tack
Ivan
I
Girolami
Jean-Pierre
JP
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage; D000818:Animals; D003928:Diabetic Nephropathies / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D019808:Losartan / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects; D011480:Protease Inhibitors / Q000008:administration & dosage; D011506:Proteins / Q000378:metabolism*; D017257:Ramipril / Q000008:administration & dosage*; D051381:Rats; D011924:Rats, Zucker; D012084:Renin-Angiotensin System / Q000187:drug effects*
C479877:AVE 7688; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006575:Heterocyclic Compounds, 3-Ring; D011480:Protease Inhibitors; D011506:Proteins; D019808:Losartan; D017257:Ramipril