title: Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes.
abstract: Diabetic nephropathy is the leading cause of end-stage renal disease. Dopamine receptors are involved in the regulation of renal hemodynamics and may play a role in diabetes-induced hyperfiltration. To test this hypothesis, we investigated the renal effect of a dopamine D3 receptor antagonist (D3-RA) in hypertensive type II diabetic SHR/N-cp rats. Lean and obese SHR/N-cp rats were randomly assigned to D3-RA, angiotensin-converting enzyme inhibitor (ACE-i), or D3-RA+ACE-i treatment or control conditions. Treated animals were given the D3-RA A-437203 (10 mg/kg/body weight (BW)/day) or the ACE-i trandolapril (0.3 mg/kg BW/day) or a combination of both. At 6 months following perfusion, fixed kidneys were analyzed by morphological and stereological methods. Indices of renal damage (glomerulosclerosis, glomerulosclerosis damage index (GSI), tubulointerstitial and vascular damage), glomerular geometry and functional variables such as urinary albumin excretion, glomerular filtration rate, blood pressure, blood chemistry and BW were determined. The GSI (score 0-4) was significantly higher (P<0.05) in untreated diabetic animals (1.62+/-0.3) compared to nondiabetic controls (0.4+/-0.2) and the treatment groups (D3-RA: 0.31+/-0.12; ACE-i: 0.29+/-0.1; combination treatment: 0.12+/-0.01). Urinary albumin excretion (mg/24 h) was higher in untreated diabetic controls (102+/-19) compared to nondiabetic controls (31+/-12) and the treatment groups (D3-RA: 44+/-15; ACE-i: 41+/-13; combination treatment: 15+/-8). Mean glomerular volume was higher in untreated diabetic animals compared to nondiabetic controls and to the treatment groups. Desmin expression, a marker of podocyte damage, was elevated in untreated diabetic controls and diminished in all treatment groups. These data suggest that in a model of type II diabetes, the dopamine D3-RA had a beneficial effect on renal morphology and albuminuria, which was comparable in magnitude to that of ACE-i treatment.
authors.affiliation: Department of Pathology, University of Heidelberg, Heidelberg, Germany. Marie-Luise_Gross@med.uni-heidelberg.de
authors.forename: Marie-Luise P
authors.initials: ML
authors.lastname: Gross
authors.forename: Andreas
authors.initials: A
authors.lastname: Koch
authors.forename: Bernd
authors.initials: B
authors.lastname: Mühlbauer
authors.forename: Marcin
authors.initials: M
authors.lastname: Adamczak
authors.forename: Heike
authors.initials: H
authors.lastname: Ziebart
authors.forename: Karla
authors.initials: K
authors.lastname: Drescher
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gross
authors.forename: Irina
authors.initials: I
authors.lastname: Berger
authors.forename: Kerstin U
authors.initials: KU
authors.lastname: Amann
authors.forename: Eberhard
authors.initials: E
authors.lastname: Ritz
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D018492:Dopamine Antagonists / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D018492:Dopamine Antagonists; D019332:Endothelin-1; D012333:RNA, Messenger; D050637:Receptors, Dopamine D3; D016212:Transforming Growth Factor beta