Trientine and renin-angiotensin system blockade ameliorate progression of glomerular morphology in hypertensive experimental diabetic nephropathy.
A comparison of the efficacy of the copper chelator, trientine, with combined renin angiotensin system (RAS) blockade on the progression of glomerular pathology in the diabetic (mREN-2)27 rat is reported. Animals were treated for 2 months with trientine, combined RAS blockers, combined trientine plus RAS blockers or none. Treatments began after inducing diabetes with streptozotocin. Physiological data were recorded monthly and light microscopic glomerular features were scored. Plasma allantoin and both plasma and renal protein carbonyls were measured as markers of oxidative stress. Trientine and RAS blockade decreased proteinuria and albuminuria and prevented an increase in creatinine clearance and kidney weight. Both reduced the diabetes-related glomerular features of mesangiolysis and glomerular segmental hypocellularity and trientine prevented severe tuft-to-capsule adhesion and reduced tubularization. Hypertension-related severe mesangial matrix expansion and global hypercellularity were increased by both treatments, which may reflect repair of mesangiolysis. Trientine reduced plasma but not renal protein carbonyls or plasma allantoin. In this model, trientine prevented the development of many diabetes-specific features similarly to RAS blockade. Amelioration of oxidative stress and features commonly observed in human diabetic nephropathy (DN), support a diabetes-related defect in copper (Cu) metabolism. The addition of Cu(II) chelation may improve current DN therapy.
Department of Medicine, University of Otago-Christchurch, Christchurch, New Zealand.
Leire
L
Moya-Olano
Helen Marie
HM
Milne
Jillian Margaret
JM
Robinson
Jonathan Vernon
JV
Hill
Christopher Miles
CM
Frampton
Helen Frances
HF
Abbott
Rufus
R
Turner
Anthony James
AJ
Kettle
Zoltán Huba
ZH
Endre
D000481:Allantoin / Q000097:blood; D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism; D003404:Creatinine / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006579:Heterozygote; D006801:Humans; D006973:Hypertension / Q000150:complications; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018384:Oxidative Stress; D011507:Proteinuria / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D013311:Streptozocin; D014266:Trientine / Q000494:pharmacology*
D002614:Chelating Agents; D000481:Allantoin; D013311:Streptozocin; D003300:Copper; D003404:Creatinine; D014266:Trientine