Original Paper Nephron Exp Nephrol 2010;114:e61–e68 DOI: 10.1159/000254567
Received: January 27, 2009 Accepted: August 10, 2009 Published online: November 4, 2009
Tesaglitazar, a Dual Peroxisome ProliferatorActivated Receptor Agonist (PPAR/), Improves Metabolic Abnormalities and Reduces Renal Injury in Obese Zucker Rats Jie Liao a Zohreh Soltani a Philip Ebenezer c Angel A. Isidro-Carrión d Rubin Zhang a Arshad Asghar a Erwin Aguilar a Joseph Francis c Xuejiao Hu b León Ferder e Efrain Reisin a a
Section of Nephrology and Hypertension, LSU Health Sciences Center, b Department of Pathology, Tulane Medical Center, New Orleans, La., and c LSU School of Veterinary Medicine, Baton Rouge, La., USA; Departments of d Pathology and e Physiology and Pharmacology, Ponce School of Medicine, Ponce, Puerto Rico
Key Words Peroxisome proliferator-activated receptor Metabolic syndrome Obese Zucker rats Renal function Kidney injury
Abstract Metabolic syndrome increases the risk of developing diabetes as well as cardiovascular and kidney diseases. This research studied the effects of tesaglitazar, a dual-acting peroxisome proliferator-activated receptor (PPAR)/ agonist, on metabolic abnormalities and kidney injury in obese Zucker rats (OZR). Lean Zucker rats (LZR) and OZR were used as control groups. Tesaglitazar (1 mol/kg/day) was given for 8 weeks in the treatment group (OZR-T). Metabolic parameters, 24-hour urine albumin excretion, and tail blood pressure were measured. Glomerular filtration rate by inulin clearance, abdominal fat and renal histology were determined at the end of the study. In comparison with the OZR and OZR-T groups, the LZR control animals’ parameters were significantly more favorable in all measures. Tesaglitazar treatment in OZR significantly reduced nonfasting glucose, C-reactive protein levels and improved dyslipidemia. Body weight, blood pressure and urine albumin excretion were
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lower, but the adjusted glomerular filtration rate higher, in the OZR-T group than in the OZR controls. Glomerular area, mesangial expansion and tubulointerstitial changes were ameliorated, and the glomerular expression of desmin was markedly more decreased in the OZR-T group than in the OZR controls. Therefore, the PPAR/ agonist tesaglitazar significantly improved metabolic abnormalities and renal function, decreased blood pressure, and protected against glomerular and interstitial damage in OZR. Copyright © 2009 S. Karger AG, Basel
Introduction
Metabolic syndrome (MS) is an increasingly common disorder characterized by central obesity, insulin resistance (IR), hypertension and dyslipidemia with elevated triglyceride and decreased high-density lipoprotein (HDL) cholesterol [1]. One recent study suggests that more than 20% of adult Americans have MS [2]. Individuals with MS are at increased risk for developing diabetes mellitus as well as renal and cardiovascular diseases, and they have higher mortality from all causes [3, 4]. MS is associated with microalbuminuria, which likely reflects Efrain Reisin, MD, FACP, FASN, Victor Chaltiel Professor of Medicine and Chief Section of Nephrology and Hypertension, Department of Internal Medicine LSU Health Sciences Center School of Medicine, 1542 Tulane Avenue New Orleans, LA 70112 (USA) Tel. +1 50 4253 4306, Fax +1 50 4471 2764, E-Mail ereisi @ lsuhsc.edu
persistent glomerular hyperfiltration and renal vascular endothelial damage [3, 4]. Obese Zucker (fa/fa) rats (OZR) have a defective leptin receptor. OZR spontaneously develop hyperlipidemia, IR, obesity and microalbuminuria at an early age; they later develop type-2 diabetes mellitus with nephropathy [5]. Therefore, they have been widely used as an animal model of diabetic nephropathy [6]. Early in life, OZR express the characteristics of MS. IR causes glucose intolerance and hyperglycemia that, if sustained, leads to glycation of protein, increased extracellular matrix and loss of renal function [4]. Hyperlipidemia also contributes to glomerular injury by increasing glomerular lipid deposits [6, 7]. Previous studies have proved that a decrease in blood pressure and the control of IR and dyslipidemia may decrease microalbuminuria, prevent the development of diabetes and have cardiovascular and renal protective benefits as well [7, 8]. Tesaglitazar, a dual-acting agonist of the peroxisome proliferator-activated receptor (PPAR)/, has been shown to correct metabolic abnormalities associated with diabetes mellitus [9–11]. In db/db mice with fully developed type II diabetes mellitus, tesaglitazar has been shown to improve IR, glycemic control and the lipid profile, and has attenuated albuminuria excretion and glomerular fibrosis as well [12]. The aims of this study were to investigate the effects of tesaglitazar in OZR, a model of obesity and type II diabetes mellitus. The treatment was initiated at the age of 20 weeks in order to study the protective role that the PPAR/ agonist may have in the development of the metabolic derangement and diabetic nephropathy that occurs in OZR. Materials and Methods Animals Heterozygous (fa/+) lean Zucker rats (LZR) and homozygous (fa/fa) OZR (19 weeks of age) were purchased from Harlan. The rats were individually housed in plastic cages and allowed free access to food and water in our animal facility. At 20 weeks of age, they were randomly divided into 3 groups: lean untreated controls (LZR-C), obese untreated controls (OZR-C) and obese rats treated with tesaglitazar (OZR-T). Tesaglitazar was given daily for 8 weeks by gastric gavage from 9 a.m. to 10 a.m. The dose of tesaglitazar (AstraZeneca, Macclesfield, UK) was 1 mol/kg/day, which had been previously reported to improve insulin sensitivity in OZR [10]. The rats in the LZR-C and OZR-C groups were gavaged with an equal volume of vehicle (0.5% carboxymethyl cellulose, 2.5 ml/kg). Each group started with 12 rats. Six from each group were sacrificed at week 20 for baseline studies, and the remaining 6 were sacrificed at week 28.
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All animals were treated following the NIH guidelines as well as the Animal Welfare Act. The experiment protocol was approved by the Louisiana State University Institutional Animal Care and Use Committee. Blood Pressure Measurement Tail-cuff systolic and diastolic blood pressures (SBP, DBP) were measured at 20, 24 and 28 weeks by an SC 1000 BP analysis system (Hatteras Instruments Inc., Cray, N.C., USA). The average of 10 readings was used as the final SBP and DBP. Urine and Blood Collection At 20, 24 and 28 weeks of age, a 24-hour urine was collected in every rat while fasting in the metabolic cage. Blood drawing was taken through the retro-orbital sinus under 3% isoflurane anesthetic after 16-hour fasting. All urine and blood samples were immediately centrifuged for 10 min at 4 ° C, and the plasma and urine samples were frozen and stored at –80 ° C until analysis. Renal Function Test As described previously [12, 13], glomerular filtration rate (GFR) by inulin clearance was measured at 20 and 28 weeks of age. Rats were anesthetized with ketamine-xylazine (45 mg and 5 mg/ kg of body weight, respectively) and placed on a heating pad to maintain rectal temperature at 37 ° C throughout the study. The right femoral vein and left femoral artery were catheterized with a polyethylene (PE-50) cannula for continuous infusion of solutions with a syringe pump and blood draw. After laparotomy, the bladder was cannulated with PE-10 tubing for urine collection and the urethra was ligated. During the first 45 min of surgery, 6% albumin was infused at a rate of 1.2 ml/100 g/h via the right femoral vein. Thereafter, saline containing 1% albumin and 7.5% inulin (Inutest; Laevosan, Linz, Austria) was infused at the same rate. After a 1-hour equilibration period, urine was collected over four 30-min periods, with blood samples being drawn at the midpoints. Plasma and urinary concentrations of inulin were analyzed by colorimetric methods [13]. Laboratory Tests Plasma total cholesterol, HDL, low-density lipoprotein and very-low-density lipoprotein (VLDL) cholesterols were quantified by a kit method (Biovision, Mountain View, Calif., USA) [14]. Plasma triglycerides were measured by an enzymatic assay from Sigma-Aldrich [15]. Blood glucose was estimated by an Ascensia Elite diabetes care system (Elkhart, Ind., USA) [16]. Urine albumins were determined by an ELISA Albuwell H kit (Exocell Inc., Philadelphia, Pa., USA). C-reactive protein (CRP) was measured by a kit method (Alpco Diagnostics, Salem, N.H., USA) [17]. Gross Organ Weight As an indicator of growth and development of the OZR, liver, heart, kidneys and abdominal pads from each rat were excised and weighed. Renal Histology Morphological analysis was assessed in 10 microscopic fields of formalin-fixed paraffin-embedded PAS-stained glass slide sections by 100! magnification with the observer blinded to the animal group. Forty glomeruli per slide were evaluated. The data were averaged. Lesion scores related to the glomerular and me-
Liao et al.
Table 1. Body and organ weights in OZR and LZR
Body weight, g Heart, g Liver, g Left kidney, g Right kidney, g Intra-abdominal fat, g Subcutaneous abdominal fat, g
LZR-C 20 weeks
LZR-C 28 weeks
OZR-C 20 weeks
OZR-C 28 weeks
OZR-T 20 weeks
OZR-T 28 weeks
448816.7* 1.180.08 12.2813.7* 1.880.23* 2.080.23* 10.581.2* 3.7480.36*
485836.1* 1.280.13 1381.46* 1.780.21* 1.780.21* 12.380.94* 5.2481.36*
655856 1.280.13 25.881.31 2.480.27 2.480.36 67.384.05 59.681.9
828832.5 1.580.06 24.282.72 2.880.20 2.680.19 100.684.17 66.682.14
635846 1.280.13 25.881.31 2.480.27 2.480.26 67.384.06 59.681.9
773874** 1.580.16 24.485.24 2.480.31** 2.280.19** 93.288.89 41.585.23**
Values are means 8 SE, n = 6. Statistical comparison between the study groups was assessed by 1-way ANOVA with repeated measurements followed by Bonferroni’s multiple comparison test. * p < 0.001 in LZR-C vs. OZR-C and OZR-T; ** p < 0.05 in OZR-T vs. OZR-C.
Table 2. GFR in OZR and LZR
GFR, ml/min/g kidney weight
LZR-C 20 weeks
LZR-C 28 weeks
OZR-C 20 weeks
OZR-C 28 weeks
OZR-T 20 weeks
OZR-T 28 weeks
1.380.1
1.1580.0
1.3980.01
0.6880.03
1.3180.02
1.2380.03**
Values are means 8 SE, n = 6. Statistical comparison between the study groups was assessed by 1-way ANOVA with repeated measurements followed by Bonferroni’s multiple comparison test. ** p < 0.05 in OZR-T vs. OZR-C.
sangial area were graded according to the following scale: 0 = preservation of the architecture, 1 = 5–15% glomerular expansion or mesangial expansion and PAS positivity, 2 = 115 to 30% glomerular expansion or mesangial expansion and PAS positivity, 3 = 130 to 50% glomerular expansion or mesangial expansion and PAS positivity, and 4 = 150% glomerular expansion or mesangial expansion and PAS positivity. Medullar tubular atrophy, interstitial inflammatory cell infiltrate and interstitial fibrosis sections were graded according to the following scale: 0 = absent, 1 = mild (involving 25% or less of each microscopic field), 2 = moderate (125 to 50%), 3 = severe (150 to 75%) and 4 = very severe (175%). When comparing various groups, the same kidney areas were analyzed [18].
cence with a Zeiss Axiovert 200 microscope. Images were captured with an Olympus Q Capture 5 camera with Q Capture Pro software. Statistical Analysis All data represent the mean 8 SD or mean 8 SE. Statistical comparison between the study groups was assessed by 1-way analysis of variance (ANOVA) with repeated measurements followed by Bonferroni’s multiple comparison test. A value of less than 0.05 was considered statistically significant.
Results Immunohistochemical Staining The desmin expression by immunofluorescence study was done with a protocol described by Khaleduzzaman et al. [19]. For the detection of podocyte damage, slides were rehydrated and incubated overnight at 4 ° C with a 1: 100 dilution of monoclonal mouse anti-human clone D33 isotype: IgG1 (Dako, Carpinteria, Calif., USA). Slides were then incubated with 5 g/ml of goat anti-Fab2 anti-mouse IgG-BT (Zymed) for 30 min, followed with 4 g/ml of streptavidin-conjugated Alexa Fluor 594 (Invitrogen) for 30 min at room temperature. Slides were mounted with ProLong Gold Antifade Reagent (Molecular Probes) and allowed to rest for at least 2 h at 4°C. Sections were viewed under epifluores-
Effect of a PPAR/ Agonist in Obese Zucker Rats
Effect of Tesaglitazar Treatment on Body Weight and Organ Weight Compared with the OZR at week 20, the LZR had a significantly (p ! 0.001) lower body weight as well as lower liver, kidney, subcutaneous fat and intra-abdominal fat weights (table 1). After 8 weeks of treatment, body weight and both the kidney and subcutaneous fat weights of the OZR-T were significantly lower than that of the agematched OZR control (p ! 0.05; table 1). Nephron Exp Nephrol 2010;114:e61–e68
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Untreated (diabetic)
Control
Treated with tesaglitazar
Fig. 1. Light microscopy of PAS staining.
Table 3. Glomerular, mesangial and tubulointerstitial architecture in OZR and LZR
Glomerular area1 Mensangial area2 Tubulointerstitial changes3
LZR-C
OZR-C
OZR-T
0 0 0
2 3 3
1 1 1
1
0 = Preservation of the architecture, 1 = 5 to 15% glomerular expansion, 2 = >15 to 30% glomerular expansion. 2 0 = Preservation of the architecture, 1 = 5 to 15% mesangial expansion and PAS positivity, 3 = >30 to 50% mesangial expansion and PAS positivity. 3 0 = Absent, 1 = mild (50 to 75% of each microscopic field).
Renal Function The absolute GFRs by inulin clearance were not significantly different among the 3 groups at 20 and 28 weeks of age, but the adjusted GFRs by kidney weight at week 28 were different. The OZR-C group had a significantly lower adjusted GFR than either the LZR-C or OZRT group (p ! 0.05; table 2).
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Glomerular Histology The LZR-C showed preservation of glomerular, mesangial and tubular interstitial histological architecture. The OZR-C, when compared with the OZR-T, showed larger glomerular area expansion of the Bowman capsule with a score of 2 versus 1, a larger percentage of mesangial matrix PAS staining of total glomerular area with a score of 3 versus 1 and patchy inflammation, loss of architecture and strong intratubular PAS staining with a score of 3 versus 1 (fig. 1; table 3). Effect of Tesaglitazar on Desmin Expression Desmin expression by immunofluorescence staining was negative in the LZR-C group at 28 weeks of age (fig. 2a); however, a strong positive staining of desmin along glomerular capillary walls was noted in the OZR-C group (fig. 2b). Compared with the OZR group, the OZRT group showed a markedly decreased intensity and distribution of desmin expression after 8 weeks of treatment (fig. 2c). Effect of Tesaglitazar on Metabolic Abnormalities Plasma Lipid Levels The total plasma cholesterol and triglycerides were much higher (p ! 0.05) in OZR-C when compared with Liao et al.
a
c
b
5 μm
Fig. 2. Immunofluorescence detection of desmin.
Table 4. Plasma lipid levels in OZR and LZR
Total cholesterol, mmol/l Triglycerides, mmol/l HDL, mmol/l VLDL, mmol/l
LZR-C 20 weeks
OZR-C 20 weeks
OZR-T 20 weeks
LZR-C 24 weeks
0.2380.008 0.5580.03 0.1980.002 0.1980.001
1.4580.06* 1.480.011** 0.4880.011 2.3280.08* 3.0280.07** 0.4580.09 0.1680.006 0.2480.007 0.2880.02 0.1680.006 0.1780.002 0.5180.01
OZR-C 24 weeks
OZR-T 24 weeks
LZR-C 28 weeks
OZR-C 28 weeks
OZR-T 28 weeks
1.5280.02* 2.6280.11* 0.7380.04* 1.1780.02*
0.7780.006** 0.6980.005 3.480.08* 1.5780.01** 1.380.08 7.1080.07* 4.0780.19** 1.0280.05** 1.3580.05** 0.4680.003 1.0480.01* 1.3380.04** 0.480.01 0.6480.03* 0.580.007** 1.0280.02**
Values are means 8 SE, n = 6. Statistical comparison between the study groups was assessed by 1-way ANOVA with repeated measurements followed by Bonferroni’s multiple comparison test. * p < 0.05 OZR-C vs. LZR-C; ** p < 0.05 OZR-T vs. OZR-C.
LZR-C at 20 weeks of age. Tesaglitazar therapy attenuated the increase in plasma total cholesterol, triglycerides and VLDL levels (p ! 0.05) from 24 to 28 weeks of age in OZR. The HDL level was increased (p ! 0.05) in OZR-T in comparison to OZR-C after 4 weeks of treatment and maintained the same significant increase (p ! 0.05) at the end of 8 weeks of treatment (table 4). Urinary Albumin Excretion The urinary albumin excretion (UAE) levels in both OZR groups were higher than those of the LZR-C group at 20, 24 and 28 weeks of age (p ! 0.01). However, when OZR were treated with tesaglitazar for 4 weeks, the UAE levels were decreased and continued to drop significantly from 8.48 mg/day to 3.99 mg/day (p ! 0.05) at the end of 8 weeks of treatment. There was no significant change in UAE in the OZR-C group after 8 weeks of vehicle administration (table 5). Blood Pressure SBP and DBP were similar in the LZR and OZR only at 20 weeks of age. Compared with the OZR-C, the SBP Effect of a PPAR/ Agonist in Obese Zucker Rats
and DBP levels were significantly decreased in OZR-T (p ! 0.05) after 4 weeks of treatment, and they remained significantly lower than in the OZR-C (p ! 0.05) until the end of study (table 5). Effect of Tesaglitazar Treatment on CRP Level At baseline, the CRP levels were significantly higher in OZR-C and OZR-T when compared with LZR-C. Plasma CRP levels in OZR were 2-fold higher than LZR-C at week 24 and 3.2-fold higher by the end of the study (week 28). OZR-T showed 0.2-fold (4 weeks) and 0.4-fold (8 weeks) reduced levels of CRP when compared with OZRC (table 6). Blood Glucose At baseline, the fasting and nonfasting glucose of OZR-C and OZR-T were significantly higher than LZR-C (p ! 0.001). Tesaglitazar therapy added no effect in the fasting blood glucose level in OZR-T, but induced a significant decrease in the nonfasting glucose level at 24 and 28 weeks (p ! 0.05; table 6).
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Table 5. UAE levels and blood pressure in OZR and LZR
UAE, mg/day SBP, mm Hg DBP, mm Hg
LZR-C 20 weeks
OZR-C 20 weeks
OZR-T 20 weeks
LZR-C 24 weeks
OZR-C 24 weeks
OZR-T 24 weeks
LZR-C 28 weeks
OZR-C 28 weeks
OZR-T 28 weeks
1.880.1 122810 9784
7.680.65* 131812 10087
8.480.84 130811 9988
1.780.1 147811 9988
6.180.6* 149810 124811*
4.2 80.4 156812 130812
1.180.01 14989 10089
5.480.50* 11988* 9988
3.180.29** 11887** 9889**
Values are means 8 SE, n = 6. Statistical comparison between the study groups was assessed by 1-way ANOVA with repeated measurements followed by Bonferroni’s multiple comparison test. * p < 0.05 OZR-C vs. LZR-C; ** p < 0.05 OZR-T vs. OZR-C.
Table 6. CRP, fasting and nonfasting blood glucose changes in OZR and LZR LZR-C 20 weeks
OZR-C 20 weeks
OZR-T 20 weeks
CRP, ng/ml 25.9080.19 51.180.26* 51.380.3 Fasting blood glucose, mg/dl 8287 11888 120811* Nonfasting blood glucose, mg/dl 102811 160810 161814*
LZR-C 24 weeks
OZR-C 24 weeks
OZR-T 24 weeks
LZR-C 28 weeks
OZR-C 28 weeks
OZR-T 28 weeks
28.1880.39 70.680.44* 59.880.2** 28.9380.33 78.780.8* 49.680.07** 7989 12189 7788 117814* 115812* 9989** 97812 122812 100811 149816* 147814* 118811**
Values are means 8 SE, n = 6. Statistical comparison between the study groups was assessed by 1-way ANOVA with repeated measurements followed by Bonferroni’s multiple comparison test. * p < 0.05 OZR-C vs. LZR-C; ** p < 0.05 OZR-T vs. OZR-C.
Discussion
PPARs (PPAR, PPAR and PPAR/) are members of a nuclear hormone receptor superfamily of ligand-dependent cellular processes, including lipid metabolism, glucose homeostasis, cell-cycle progression, cell differentiation, inflammation and extracellular matrix remodeling [20]. PPAR primarily regulates the expression of genes encoding enzymes and transport proteins in the liver, heart and kidneys controlling the lipid homeostasis. It stimulates fatty acid (FA) oxidation and also improves lipoprotein metabolism by reducing the VLDL level and enhancing the catabolism of triglyceride-rich lipoprotein particles. In addition, PPAR modulates the expression of HDL apolipoprotein genes and has a direct effect on macrophage cholesterol efflux transporters [21, 22]. PPAR promotes pre-adipocyte differentiation, stimulates the storage of FAs in adipocytes and enhances insulin sensitivity. The action of PPAR on insulin sensitivity results from its ability to channel FAs into adipose tissue, thus decreasing plasma FA concentration. In addition, PPAR can affect insulin sensitivity by regulating adipocyte hormones, cytokines and proteins that are involved in IR and that alleviate lipotoxicity in the skeletal muscles, liver and pancreas [21, 22]. Simultaneous activation of PPAR and receptors might alter the tissue distribution of FAs by stimulating e66
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their uptake and utilization in adipose tissue, liver and skeletal muscle. As a result, PPAR increases insulinstimulated glucose disposal in skeletal muscle, ameliorates IR and decreases fat load in adipose tissue in rodents [11–23]. Another complementary mechanism of combined activation of PPAR and when improving IR involves the induction of adipose tissue adiponectin receptors by PPAR and adiponectin by PPAR, resulting in decreased infiltration of macrophages in adipose tissue, thereby ameliorating tissue inflammation and improving obesity-induced IR [24]. Finally, it has been reported that the PPAR agonist decreases food intake and fat deposits induced by the PPAR agonist [25], even though an earlier study showed a small increase in body weight in patients who received tesaglitazar [11]. Dual PPAR/ agonists may represent a new therapy for type 2 diabetes and MS. Beneficial metabolic effects of glitazars have been demonstrated in animal studies [9, 10, 12, 26–28]. The present research examined the effects of a PPAR/ agonist, tesaglitazar, in OZR, an animal model of obesity and diabetic nephropathy. The results of this study showed that OZR treated with oral tesaglitazar for 8 weeks significantly reduced nonfasting glucose and improved dyslipidemia when compared with control OZR. Tesaglitazar therapy also lowered SBP and DBP as well as body weight and subLiao et al.
cutaneous abdominal fat weight, probably due to the improvement of IR. Earlier studies have shown that increased sympathetic nervous system and renin-angiotensin system activity along with the IR and hyperinsulinemia that occur in obesity cause hypertension [29, 30]. Improving insulin sensitivity and controlling hyperglycemia or dyslipidemia has a positive effect on blood pressure control [27, 31, 32]. Consequently, in our study, the improvement of the metabolic derangement following treatment with tesaglitazar may explain the reduction in blood pressure that occurs in OZR-T. Other main findings in our study of OZR treated with tesaglitazar were low CRP levels and decreased UAE. Recently, CRP, an inflammatory indicator, has been discovered to be a powerful independent marker for the development of cardiovascular disease and may really be a reflection of significant endothelial damage [33]. Microalbuminuria, a significant risk factor for progressive renal disease, is associated with IR, hyperinsulinemia, central obesity, dyslipidemia and systolic hypertension [34– 36]. Previous studies [5, 6] have shown that the earliest known lesion in OZR with nephropathy involves glomerular podocytes, as evidenced by glomerular edge immunohistochemical staining for desmin, and that this type of damage is best explained by hyperlipidemia [6]. Our findings in OZR showed that tesaglitazar improves the glomerular and interstitial architecture and the podocyte damage, benefits that may be explained not only by the decrease in blood pressure, but also by the glycemic, lipidemic and anti-inflammatory protective controls induced by the use of a dual PPAR/ agonist [37, 38]. Thus, we have demonstrated that in OZR, tesaglitazar significantly decreases blood pressure, improves metabolic abnormalities and renal function, and reduces kidney injury. References
Effect of a PPAR/ Agonist in Obese Zucker Rats
The same positive effect was previously demonstrated in a db/db mice model of diabetic nephropathy [12]. Our research, however, used the OZR, another model of type 2 diabetes mellitus, and we were able to document not only the improvement in the metabolic derangement and in the kidney histological architecture, but also in the glomerular function measured by inulin clearance. The measurement of GFR with inulin prevents the inaccuracy of serum creatinine determination and its derived creatinine clearance that may be caused by the variability in muscle mass, glucose and plasma lipid levels among the different groups studied. The clinical development of tesaglitazar was discontinued in May 2006 following phase III clinical trial results because its benefit-risk profile did not provide a significant advantage over existing antidiabetic therapies. Nevertheless, the beneficial effects of tesaglitazar on glucose, lipid, BP, inflammation and, more importantly, protection of the renal function and structure, as demonstrated in this study, suggest that the development of novel dual PPAR/ agonists for the treatment of patients with MS and type II diabetes remains an attractive therapeutic avenue for exploration.
Acknowledgments This work was supported by the Investigators Sponsor Program from AstraZeneca. Part of this study was presented at the 22nd Annual Scientific Meeting of the American Society of Hypertension Inc.
Disclosures Efrain Reisin, MD, had research contracts and has been a member of an advisory board for AstraZeneca.
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