Effects of CP-900691, a novel peroxisome proliferator-activated receptor α, agonist on diabetic nephropathy in the BTBR ob/ob mouse.

Abstract

Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF(2α), a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF(2α) excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF(2α), possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy.

• Authors: Bardia Askari, Tomasz Wietecha, Kelly L Hudkins, Edward J Fox, Kevin D O'Brien, Jinkyu Kim, Tri Q Nguyen, Charles E Alpers
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 94 Issue 8 Pg. 851-62 (Aug 2014) ISSN: 1530-0307 [Electronic] United States
• PMID: 24955894 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 3-(3-(1-carboxy-1-methylethoxy)phenyl)piperidine-1-carboxylic acid 4-trifluoromethylbenzyl ester
• Anti-Obesity Agents
• Hypoglycemic Agents
• Hypolipidemic Agents
• PPAR alpha
• Piperidines
• Propionates
• 8-epi-prostaglandin F2alpha
• Dinoprost

Topics

• Albuminuria (complications, physiopathology, prevention & control)
• Animals
• Anti-Obesity Agents (adverse effects, therapeutic use)
• Diabetes Mellitus, Type 2 (complications, drug therapy, immunology, metabolism)
• Diabetic Nephropathies (complications, physiopathology, prevention & control)
• Dinoprost (agonists, analogs & derivatives, urine)
• Disease Progression
• Female
• Glomerular Mesangium (drug effects, immunology, metabolism, pathology)
• Hypercholesterolemia (chemically induced, complications, physiopathology, prevention & control)
• Hypertriglyceridemia (complications, prevention & control)
• Hypertrophy
• Hypoglycemic Agents (adverse effects, therapeutic use)
• Hypolipidemic Agents (adverse effects, therapeutic use)
• Insulin Resistance
• Kidney (drug effects, immunology, metabolism, pathology)
• Mice
• Mice, Inbred Strains
• Mice, Obese
• Obesity (complications, prevention & control)
• PPAR alpha (agonists, metabolism)
• Piperidines (adverse effects, therapeutic use)
• Propionates (adverse effects, therapeutic use)