title: The effects of dual PPARα/γagonism compared with ACE inhibition in the BTBRob/ob mouse model of diabetes and diabetic nephropathy.
abstract: The leptin-deficient BTBRob/ob mouse develops progressive albuminuria and morphological lesions similar to human diabetic nephropathy (DN), although whether glomerular hyperfiltration, a recognized feature of early DN that may contribute to renal injury, also occurs in this model is not known. Leptin replacement has been shown to reverse the signs of renal injury in this model, but in contrast, the expected renoprotection by angiotensin-converting enzyme (ACE) inhibition in BTBRob/ob mice seems to be limited. Therefore, to investigate the potential renal benefits of improved metabolic control in this model, we studied the effect of treatment with the dual peroxisome proliferator-activated receptor (PPAR)α/γagonist AZD6610 and compared it with the ACE inhibitor enalapril. AZD6610 lowered plasma glucose and triglyceride concentrations and increased liver size, but had no significant effect in reducing albuminuria, whereas enalapril did have an effect. Nephrin and WT1 mRNA expression decreased in the kidneys of BTBRob/ob mice, consistent with podocyte injury and loss, but was unaffected by either drug treatment: at the protein level, both nephrin and WT1-positive cells per glomerulus were decreased. Mesangial matrix expansion was reduced in AZD6610-treated mice. GFR, measured by creatinine clearance, was increased in BTBRob/ob mice, but unaffected by either treatment. Unexpectedly, enalapril-treated mice showed intrarenal arteriolar vascular remodeling with concentric thickening of vessel walls. In summary, we found that the BTBRob/ob mouse model shows some similarities to the early changes seen in human DN, but that ACE inhibition or PPARα/γagonism afforded limited or no kidney protection.
authors.affiliation: Cardiovascular & Metabolic Disease Innovative Medicines, AstraZeneca R&D Gothenburg, Mölndal, Sweden anette.e.ericsson@astrazeneca.com.
authors.forename: Anette
authors.initials: A
authors.lastname: Ericsson
authors.affiliation: Cardiovascular & Metabolic Disease Innovative Medicines, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Tonelius
authors.affiliation: Cardiovascular & Metabolic Disease Innovative Medicines, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Mark
authors.initials: M
authors.lastname: Lal
authors.affiliation: Cardiovascular & Metabolic Disease Innovative Medicines, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Alan
authors.initials: A
authors.lastname: Sabirsh
authors.affiliation: Drug, Safety & Metabolism, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Böttcher
authors.affiliation: Cardiovascular & Metabolic Disease Innovative Medicines, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: William-Olsson
authors.affiliation: Cardiovascular & Metabolic Disease Innovative Medicines, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Strömstedt
authors.affiliation: Drug, Safety & Metabolism, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Camilla
authors.initials: C
authors.lastname: Johansson
authors.affiliation: Drug, Safety & Metabolism, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Gina
authors.initials: G
authors.lastname: Hyberg
authors.affiliation: Discovery Sciences Innovative Medicines Research Unit, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Tapani
authors.affiliation: Cardiovascular & Metabolic Disease Innovative Medicines, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Ann-Cathrine
authors.initials: AC
authors.lastname: Jönsson-Rylander
authors.affiliation: Cardiovascular & Metabolic Disease Innovative Medicines, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Unwin
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D003920:Diabetes Mellitus / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D004195:Disease Models, Animal; D004656:Enalapril / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D047493:PPAR alpha / Q000037:antagonists & inhibitors*; D047495:PPAR gamma / Q000037:antagonists & inhibitors*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D025721:WT1 Proteins
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001786:Blood Glucose; D008565:Membrane Proteins; D047493:PPAR alpha; D047495:PPAR gamma; D012097:Repressor Proteins; D014280:Triglycerides; D025721:WT1 Proteins; C000602896:WT1 protein, mouse; C113267:nephrin; D004656:Enalapril
keywords: BTBRob/ob mouse; angiotensin‐converting enzyme; diabetic kidney disease; peroxisome proliferator‐activated receptor