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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 alters albuminuria and urinary ROS excretion in BTBR WT, but not in BTBR ob/ob miceBTBR WT and BTBR ob/ob were treated with or without CP for 14 weeks (BTBR WT, n=8; BTBR ob/ob, n=9; BTBR WT + CP, n=9; BTBR ob/ob + CP, n=9). Urinary volume (A), daily albumin (B), albumin: creatinine ratio (ACR) (C) and 8-epi concentrations (D) were measured as described in Methods (BTBR; open bars, BTBR ob/ob; closed bars). Results are shown as means ± SEM. Statistical analysis was performed via one-way ANOVA followed by Newman-Keuls post-test. *P < 0.01 vs. BTBR WT; #P < 0.05 vs. BTBR ob/ob.
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Figure 4: CP-900691 alters albuminuria and urinary ROS excretion in BTBR WT, but not in BTBR ob/ob miceBTBR WT and BTBR ob/ob were treated with or without CP for 14 weeks (BTBR WT, n=8; BTBR ob/ob, n=9; BTBR WT + CP, n=9; BTBR ob/ob + CP, n=9). Urinary volume (A), daily albumin (B), albumin: creatinine ratio (ACR) (C) and 8-epi concentrations (D) were measured as described in Methods (BTBR; open bars, BTBR ob/ob; closed bars). Results are shown as means ± SEM. Statistical analysis was performed via one-way ANOVA followed by Newman-Keuls post-test. *P < 0.01 vs. BTBR WT; #P < 0.05 vs. BTBR ob/ob.

Mentions: In order to assess the efficacy of CP on DN, we analyzed urinary albumin, creatinine, glucose and 8-epi excretion in CP-treated and untreated BTBR WT and BTBR ob/ob mice. Daily urinary creatinine was elevated in BTBR ob/ob mice (0.565 ± 0.06 mg/24hr vs. 0.989 ± 0.2 mg/24hr, P<0.05, BTBR WT vs. BTBR ob/ob), and CP treatment had no effect on either BTBR WT (0.565 ± 0.06 mg/24hr vs. 0.445 ± 0.059, P=0.1501, BTBR WT vs. BTBR WT + CP) or BTBR ob/ob mice (0.989 ± 0.2 mg/24hr vs. 1.050 ± 0.1 mg/24 hr, P=0.7756, BTBR ob/ob vs. BTBR ob/ob + CP). Surprisingly, CP-treated BTBR WT mice had pronounced albuminuria (Fig. 4B, C), despite having normal urine flow (Fig. 4A). BTBR ob/ob mice were polyuric (Fig. 4A), albuminuric (Fig. 4B-C) and glycosuric, measured as the % fractional excretion of glucose (% FEGlc) (0.49 ± 0.04 % vs. 2.71 ± 0.73, BTBR WT vs. BTBR ob/ob, P<0.01). In BTBR ob/ob mice, CP had an anti-diuretic effect (Fig. 4A), and abolished glycosuria (2.71 ± 0.73 % vs. 0.80 ± 0.06 %, BTBR ob/ob vs. BTBR ob/ob + CP, P<0.001). Despite these improvements, CP treatment had no effect on the albuminuria in BTBR ob/ob mice (Fig. 4B-C).


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 alters albuminuria and urinary ROS excretion in BTBR WT, but not in BTBR ob/ob miceBTBR WT and BTBR ob/ob were treated with or without CP for 14 weeks (BTBR WT, n=8; BTBR ob/ob, n=9; BTBR WT + CP, n=9; BTBR ob/ob + CP, n=9). Urinary volume (A), daily albumin (B), albumin: creatinine ratio (ACR) (C) and 8-epi concentrations (D) were measured as described in Methods (BTBR; open bars, BTBR ob/ob; closed bars). Results are shown as means ± SEM. Statistical analysis was performed via one-way ANOVA followed by Newman-Keuls post-test. *P < 0.01 vs. BTBR WT; #P < 0.05 vs. BTBR ob/ob.
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Figure 4: CP-900691 alters albuminuria and urinary ROS excretion in BTBR WT, but not in BTBR ob/ob miceBTBR WT and BTBR ob/ob were treated with or without CP for 14 weeks (BTBR WT, n=8; BTBR ob/ob, n=9; BTBR WT + CP, n=9; BTBR ob/ob + CP, n=9). Urinary volume (A), daily albumin (B), albumin: creatinine ratio (ACR) (C) and 8-epi concentrations (D) were measured as described in Methods (BTBR; open bars, BTBR ob/ob; closed bars). Results are shown as means ± SEM. Statistical analysis was performed via one-way ANOVA followed by Newman-Keuls post-test. *P < 0.01 vs. BTBR WT; #P < 0.05 vs. BTBR ob/ob.
Mentions: In order to assess the efficacy of CP on DN, we analyzed urinary albumin, creatinine, glucose and 8-epi excretion in CP-treated and untreated BTBR WT and BTBR ob/ob mice. Daily urinary creatinine was elevated in BTBR ob/ob mice (0.565 ± 0.06 mg/24hr vs. 0.989 ± 0.2 mg/24hr, P<0.05, BTBR WT vs. BTBR ob/ob), and CP treatment had no effect on either BTBR WT (0.565 ± 0.06 mg/24hr vs. 0.445 ± 0.059, P=0.1501, BTBR WT vs. BTBR WT + CP) or BTBR ob/ob mice (0.989 ± 0.2 mg/24hr vs. 1.050 ± 0.1 mg/24 hr, P=0.7756, BTBR ob/ob vs. BTBR ob/ob + CP). Surprisingly, CP-treated BTBR WT mice had pronounced albuminuria (Fig. 4B, C), despite having normal urine flow (Fig. 4A). BTBR ob/ob mice were polyuric (Fig. 4A), albuminuric (Fig. 4B-C) and glycosuric, measured as the % fractional excretion of glucose (% FEGlc) (0.49 ± 0.04 % vs. 2.71 ± 0.73, BTBR WT vs. BTBR ob/ob, P<0.01). In BTBR ob/ob mice, CP had an anti-diuretic effect (Fig. 4A), and abolished glycosuria (2.71 ± 0.73 % vs. 0.80 ± 0.06 %, BTBR ob/ob vs. BTBR ob/ob + CP, P<0.001). Despite these improvements, CP treatment had no effect on the albuminuria in BTBR ob/ob mice (Fig. 4B-C).

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