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

Askari B, Wietecha T, Hudkins KL, Fox EJ, O'Brien KD, Kim J, Nguyen TQ, Alpers CE - Lab. Invest. (2014)

Bottom Line: Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pathology, University of Washington, Seattle, WA, USA [2] Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, New York, NY, USA.

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.

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CP-900691-induced effects in the expression of genes associated with β-oxidation and mitochondrial homeostasis in RNA extracted from the renal cortex of BTBR WT and BTBR ob/ob miceRT-qPCR was used to determine the relative expression of genes associated with β-oxidation and mitochondrial homeostasis. BTBR WT, open bars (BTBR WT; n=4, BTBR WT + CP; n=4) BTBR ob/ob, closed bars (BTBR ob/ob; n=5, BTBR ob/ob + CP; n=5). Results are shown as means ± SEM. When statistically justified, gene expression values were log-transformed prior to statistical analysis. Statistical analysis was performed via one-way ANOVA followed by Newman-Keuls post-test. *P < 0.05 vs. BTBR WT; #P < 0.05 vs. BTBR ob/ob.
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Figure 6: CP-900691-induced effects in the expression of genes associated with β-oxidation and mitochondrial homeostasis in RNA extracted from the renal cortex of BTBR WT and BTBR ob/ob miceRT-qPCR was used to determine the relative expression of genes associated with β-oxidation and mitochondrial homeostasis. BTBR WT, open bars (BTBR WT; n=4, BTBR WT + CP; n=4) BTBR ob/ob, closed bars (BTBR ob/ob; n=5, BTBR ob/ob + CP; n=5). Results are shown as means ± SEM. When statistically justified, gene expression values were log-transformed prior to statistical analysis. Statistical analysis was performed via one-way ANOVA followed by Newman-Keuls post-test. *P < 0.05 vs. BTBR WT; #P < 0.05 vs. BTBR ob/ob.

Mentions: The metabolic burden of diabetes has been associated with mitochondrial dysfunction. We analyzed mRNA expression of genes associated with β-oxidation, namely acox1, cpt1a and cpt2, and genes associated with mitochondrial function and biogenesis, namely uncoupling protein 2 (ucp2) and sirtuin 1 (sirt1) (30, 31), from the renal cortex of treated and untreated BTBR WT and BTBR ob/ob mice. Unlike the liver, there were no changes in the expression of acox1, cpt1a and cpt2 (Fig. 6A-C) in BTBR ob/ob kidneys. However, ucp2 and sirt1 expression were increased (Fig. 6D, 6E). CP treatment increased acox1 and ucp2 in BTBR WT mice (Fig. 6A. 6D), but did not have any effects on acox1, cpt1a and cpt2 expression in the ob/ob. However, CP treatment abolished the elevated sirt1 expression in the BTBR ob/ob mice (Fig. 6D)


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

Askari B, Wietecha T, Hudkins KL, Fox EJ, O'Brien KD, Kim J, Nguyen TQ, Alpers CE - Lab. Invest. (2014)

CP-900691-induced effects in the expression of genes associated with β-oxidation and mitochondrial homeostasis in RNA extracted from the renal cortex of BTBR WT and BTBR ob/ob miceRT-qPCR was used to determine the relative expression of genes associated with β-oxidation and mitochondrial homeostasis. BTBR WT, open bars (BTBR WT; n=4, BTBR WT + CP; n=4) BTBR ob/ob, closed bars (BTBR ob/ob; n=5, BTBR ob/ob + CP; n=5). Results are shown as means ± SEM. When statistically justified, gene expression values were log-transformed prior to statistical analysis. Statistical analysis was performed via one-way ANOVA followed by Newman-Keuls post-test. *P < 0.05 vs. BTBR WT; #P < 0.05 vs. BTBR ob/ob.
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Related In: Results  -  Collection

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Figure 6: CP-900691-induced effects in the expression of genes associated with β-oxidation and mitochondrial homeostasis in RNA extracted from the renal cortex of BTBR WT and BTBR ob/ob miceRT-qPCR was used to determine the relative expression of genes associated with β-oxidation and mitochondrial homeostasis. BTBR WT, open bars (BTBR WT; n=4, BTBR WT + CP; n=4) BTBR ob/ob, closed bars (BTBR ob/ob; n=5, BTBR ob/ob + CP; n=5). Results are shown as means ± SEM. When statistically justified, gene expression values were log-transformed prior to statistical analysis. Statistical analysis was performed via one-way ANOVA followed by Newman-Keuls post-test. *P < 0.05 vs. BTBR WT; #P < 0.05 vs. BTBR ob/ob.
Mentions: The metabolic burden of diabetes has been associated with mitochondrial dysfunction. We analyzed mRNA expression of genes associated with β-oxidation, namely acox1, cpt1a and cpt2, and genes associated with mitochondrial function and biogenesis, namely uncoupling protein 2 (ucp2) and sirtuin 1 (sirt1) (30, 31), from the renal cortex of treated and untreated BTBR WT and BTBR ob/ob mice. Unlike the liver, there were no changes in the expression of acox1, cpt1a and cpt2 (Fig. 6A-C) in BTBR ob/ob kidneys. However, ucp2 and sirt1 expression were increased (Fig. 6D, 6E). CP treatment increased acox1 and ucp2 in BTBR WT mice (Fig. 6A. 6D), but did not have any effects on acox1, cpt1a and cpt2 expression in the ob/ob. However, CP treatment abolished the elevated sirt1 expression in the BTBR ob/ob mice (Fig. 6D)

Bottom Line: Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pathology, University of Washington, Seattle, WA, USA [2] Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, New York, NY, USA.

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.

Show MeSH
Related in: MedlinePlus