* Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama, Second Department of Medicine, Asahikawa Medical College, Asahikawa, Hokkaido, and || Division of Endocrinology & Metabolism, Kanazawa Medical University, Kahoku-Gun, Ishikawa, Japan
Correspondence: Dr. Daisuke Koya, Division of Endocrinology & Metabolism, Kanazawa Medical University, Kahoku-Gun, Ishikawa 920-0293, Japan. Phone: +81-76-286-2211; Fax: +81-76-286-6927; E-mail: koya0516{at}kanazawa-med.ac.jp
Received for publication January 23, 2007.
Accepted for publication June 7, 2007.
Metabolic syndrome is associated with increased risk of chronickidney disease, and the renal injury in patients with metabolicsyndrome may be a result of altered renal lipid metabolism.We fed wild-type or insulin-sensitive heterozygous peroxisomeproliferator–activated receptor –deficient (PPAR+/–)mice a high-fat diet for 16 weeks. In wild-type mice, this dietinduced core features of metabolic syndrome, subsequent renallipid accumulation, and renal injury including glomerulosclerosis,interstitial fibrosis, and albuminuria. Renal lipogenesis accelerated,determined by increased renal mRNA expression of the lipogenicenzymes fatty acid synthase and acetyl-CoA carboxylase (ACC)and by increased ACC activity. In addition, renal lipolysiswas suppressed, determined by reduced mRNA expression of thelipolytic enzyme carnitine palmitoyl acyl-CoA transferase 1and by reduced activity of AMP-activated protein kinase. InPPAR+/– mice, renal injury, systemic metabolic abnormalities,renal accumulation of lipids, and the changes in renal lipidmetabolism were attenuated. Thus, a high-fat diet leads to analtered balance between renal lipogenesis and lipolysis, subsequentrenal accumulation of lipid, and renal injury. We suggest thatrenal lipid metabolism could serve as a new therapeutic targetto prevent chronic kidney disease in patients with metabolicsyndrome.
Metabolic syndrome, which is characterized by concurrent existenceof obesity, dyslipidemia, hyperinsulinemia, hyperglycemia, andhypertension, is increasingly common because of increased prevalenceof obesity. This syndrome is a growing health problem becauseof the associated increased risk for cardiovascular diseaseand premature death.1,2 Furthermore, a recent report suggestedthat individuals with metabolic syndrome are also at increasedrisk for developing chronic kidney diseases (CKD).3
Several pathomechanisms underlying the development of renalinjury in metabolic syndrome have been proposed.4–8 Amongthem, renal lipid accumulation, lipotoxicity, has been reportedto play an important role in the pathogenesis of renal injuryin metabolic syndrome, although the precise mechanism of renallipid accumulation has not been fully elucidated.9–12Excess energy intake, including high-fat diet (HFD), contributesto the development of metabolic syndrome. HFD also causes renallipid accumulation and renal injury.13 Therefore, elucidationof precise mechanisms that are responsible for renal lipid accumulationunder an HFD could suggest the possible mechanisms underlyingthe development of renal injury in metabolic syndrome and thusenhance the design of novel therapeutic strategies against thisrenal injury.
Various intracellular molecules regulate local lipid metabolismin several tissues, such as skeletal muscle and liver.14–17Under an altered systemic glucose and lipid metabolism, theimbalance between lipogenesis and lipolysis in such tissuescontributes to the local lipid accumulation and subsequent pathophysiologicchanges.16,18,19 However, in the kidney, the role of local lipidmetabolism in lipid accumulation and subsequent renal injuryin metabolic syndrome has not been fully determined.
The purpose of this study was to clarify further the role ofrenal lipid metabolism in the development of renal injury inmetabolic syndrome. We first examined how HFD could affect renallipid metabolism. We especially focused on the balance betweenlipogenesis and lipolysis in the kidney per se. Furthermore,we investigated how favorable systemic metabolic conditionsunder an HFD can affect renal lipid metabolism and renal injuryby using heterozygous peroxisome proliferator–activatedreceptor-–deficient (PPAR-+/–) mice, which werepreviously reported to be protected against HFD-induced obesityand insulin resistance.
Systemic Metabolic Abnormalities
The characteristics of the four groups at 16 wk of experimentalperiod are presented in Table 1. PPAR-+/+ mice on an HFD weresignificantly heavier than PPAR-+/+ mice on a low-fat diet (LFD).These obese mice showed significantly high plasma triglycerides,cholesterol, TNF- and monocyte chemoattractant protein-1 (MCP-1)levels, compared with their counterparts on an LFD. Plasma adiponectinlevels in PPAR-+/+ mice on an HFD were significantly lower thanin PPAR-+/+ mice on an LFD. Moreover, PPAR-+/+ mice on an HFDshowed hyperinsulinemia during 4 wk of HFD (Figure 1A) and hyperglycemiaduring 8 wk of HFD (Figure 1B). In contrast, PPAR-+/–mice were significantly protected against obesity, insulin resistance,and the altered adipokine secretions during the 16-wk HFD, althoughno differences in food intake were observed between PPAR-+/+and PPAR-+/– mice (Table 1, Figure 1, A and B). Glucoseintolerance (determined by intraperitoneal glucose tolerancetest) and insulin resistance (determined by intraperitonealinsulin tolerance test) at 16 wk of HFD in PPAR-+/+ mice wereattenuated in PPAR-+/– mice (Figure 1, C and D). PPAR-+/+mice showed features of metabolic syndrome from the early stageof HFD, whereas these alterations under an HFD were attenuatedin insulin-sensitive PPAR-+/– mice, as previously reported.20,21
Figure 1. (A) Plasma insulin levels during 16-wk experimental period in each group of mice. Data are means ± SEM for five to 11 mice in each group. (B) Fasting blood glucose during 16-wk experimental period in each group of mice. Data are means ± SEM for 11 mice in each group. (C) Glucose tolerance test at the 16-wk experimental period in each group of mice. Data are means ± SEM for seven mice in each group. (D) Insulin tolerance test at the 16-wk experimental period in each group of mice. Data are means ± SEM for seven mice in each group. *P < 0.05 versus PPAR-+/+ mice on an LFD; P < 0.05 versus PPAR-+/– mice on an HFD.
Renal Injuries
We confirmed the significant downregulation of mRNA expressionof PPAR- in the kidneys of PPAR-+/– mice on both diets,compared with PPAR-+/+ mice (Table 2). Under an HFD, PPAR-+/+mice exhibited a significant rise in urinary albumin excretionat 16 wk, although no significant differences were observedamong the four groups at 4 and 8 wk (Figure 2). The increasein urinary albumin excretion at 16 wk was significantly inhibitedin PPAR-+/– mice on an HFD (Figure 2). Examination ofrenal histopathologic changes with periodic acid-Schiff (PAS)in four groups revealed that HFD induced mesangial expansionin PPAR-+/+ mice (Figure 3, B and M). The expression of fibronectinwas significantly increased in both the glomeruli and interstitiumof PPAR-+/+ mice on an HFD (Figure 3, F and N, and J and O).In contrast, these HFD-induced glomerular and interstitial lesionswere significantly attenuated in PPAR-+/– mice (Figure 3,D and M, H and N, and L and O). In both PPAR+/+ and PPAR+/–on an LFD, glomerular and interstitial lesions were not observed(Figure 3, A, C, E, G, I, and K). Furthermore, under an HFD,the mRNA expression levels of fibronectin, type IV collagen,plasminogen activator-1, and MCP-1 were significantly increasedin the renal cortex of PPAR-+/+ mice, and these changes weresignificantly attenuated in PPAR-+/– mice (Table 2).
Figure 2. Twenty-four-hour urinary albumin excretion during the 16-wk experimental period in each group of mice. Data are means ± SEM for six to 11 mice in each group. *P < 0.05 versus PPAR-+/+ mice on an LFD; P < 0.05 versus PPAR-+/– mice on an HFD.
Figure 3. (A through D) Representative photomicrographs of PAS-stained kidney sections from mice in each group. (E through H) Representative photomicrographs of glomeruli of kidney sections immunostained for fibronectin. (I through L) Representative photomicrographs of interstitium of kidney sections immunostained for fibronectin. (M) Quantitative analysis of mesangial area from 20 glomeruli per mouse. Data are means ± SEM for 11 mice in each group. (N) Quantitative analysis of fibronectin score from 20 glomeruli per mouse. Data are means ± SEM for 11 mice in each group. (O) Quantitative analysis of fibronectin score from 20 random fields per mouse. Data are means ± SEM for 11 mice in each group. *P < 0.05 versus PPAR-+/+ mice on an LFD; P < 0.05 versus PPAR-+/– mice on an HFD. Magnifications: x400 in A through H; x200 in I through L.
Renal Lipid Accumulation
Increased renal triglyceride content was observed in PPAR-+/+mice at 8 and 16 wk of HFD, although no significant increasewas observed at 4 wk of HFD (Figure 4A). Furthermore, HFD-inducedincreases in renal triglyceride content at 8 and 16 wk of HFDwere significantly reduced in PPAR-+/– mice (Figure 4A).During the experimental period, no significant differences inrenal cholesterol content were observed among the four groups(Figure 4B). Oil-Red O staining of kidney sections in the fourgroups revealed that HFD caused marked neutral lipid accumulationsin both the glomerular and tubulointerstitial lesion (Figure 5,B and F). These accumulations were markedly decreased in PPAR-+/–mice (Figure 5, D and H). In both PPAR+/+ and PPAR+/–on an LFD, these renal neutral lipid accumulations were notobserved (Figure 5, A, C, E, and G).
Figure 4. Triglyceride (A) and cholesterol (B) contents in the kidneys of mice in each group. Data are means ± SEM for five to 11 mice in each group. *P < 0.05 versus PPAR-+/+ mice on an LFD; P < 0.05 versus PPAR-+/– mice on an HFD.
Figure 5. (A through H) Representative photomicrographs of Oil-Red O–stained kidney sections in each group of mice. Magnifications: x200 in A through D; x400 in E through H.
Renal Lipid Metabolism
Sterol regulatory element-binding protein-1c (SREBP-1c) is atranscriptional factor that regulates the transcriptional activityof the enzymes that are involved in lipogenesis, fatty acidsynthase (FAS) and acetyl-CoA carboxylase (ACC).17,22 In thekidneys from all four groups, we measured the mRNA expressionsof SREBP-1c, FAS, and ACC at 4 and 16 wk. The mRNA expressionlevels of these molecules were increased in the kidneys of PPAR-+/+mice on an HFD at both time points (Tables 2 and 3). However,these changes were not observed in PPAR-+/– mice (Tables 2and 3). Furthermore, under an HFD, ACC protein content was increasedin the kidneys of PPAR-+/+ mice at 16 wk but not in PPAR-+/–mice (Figure 6, A and B).
Figure 6. (A) Representative immunoblots of phospho-AMPK(Thr172), AMPK, phospho-ACC(Ser79), and ACC in the protein extractions from renal cortex of mice in each group. -Actin was loaded as an internal control. (B) Quantitative analysis of ACC protein expression. (C) Quantitative analysis of phospho-AMPK(Thr172). (D) Quantitative analysis of phospho-ACC(Ser79). Data are means ± SEM for five to eight mice in each group. *P < 0.05 versus PPAR-+/+ mice on an LFD; P < 0.05 versus PPAR-+/– mice on an HFD.
We next measured the mRNA expression levels of the moleculesthat are involved in lipolysis. At both 4 and 16 wk, we didnot observe any differences in mRNA expression levels of PPAR-,acyl-CoA oxidase, (ACO), and acyl-COA dehydrogenase (MCAD) inthe kidneys among the four groups (Tables 2 and 3). However,at both 4 and 16 wk of HFD, a significant decrease in mRNA expressionof carnitine palmitoyl transferase-1 (CPT-1) in the kidney ofPPAR-+/+ mice was observed, although this was not found in PPAR-+/–mice (Tables 2 and 3).
The 5' AMP-activated protein kinase (AMPK) phosphorylates andinactivates ACC, resulting in a decrease in intracellular levelof malonyl-CoA, thereby relieving inhibition of CPT-1 activityand accelerating lipolysis.23 Phosphorylation of both AMPK(Thr172)(Figure 6, A and C) and ACC(Ser79) (Figure 6, A and D) weresignificantly decreased in the kidneys of PPAR-+/+ mice on anHFD at 16 wk. In contrast, these HFD-induced decreases in phosphorylationof AMPK(Thr172) (Figure 6, A and C) and ACC(Ser79) (Figure 6,A and D) were not observed in the PPAR-+/– mice.
Here, we show that HFD induces the alteration of renal lipidmetabolism by an imbalance between lipogenesis and lipolysisin the kidney per se, as well as systemic metabolic abnormalitiesand subsequent renal lipid accumulation and renal injury. Furthermore,these renal involvements under an HFD are ameliorated in insulin-sensitivePPAR-+/– mice.
Recently, HFD was reported to induce renal injury, althoughthe exact mechanisms have not been fully clarified.13,24 Severalreports have suggested that renal lipid accumulation, lipotoxicity,is associated with the development of such renal injury.13 Itis interesting that our results show that HFD induces systemicmetabolic abnormalities such as insulin resistance during 4wk of HFD and subsequent renal lipid accumulation during 8 wkof HFD and finally renal injury at 16 wk of HFD. Furthermore,these HFD-induced renal involvements are ameliorated in insulin-sensitivePPAR-+/– mice. These results suggest that lipotoxicityin the kidney could be one of the important mechanisms for thedevelopment of renal injury associated with metabolic syndrome.
To date, the precise mechanisms for renal lipid accumulationhave not been fully determined. However, there is growing evidencethat the increased renal lipogenesis plays a role in the pathogenesisof renal injury.11,13,25,26 Therefore, we investigated whetherHFD increases renal mRNA expression levels of SREBP-1c, FAS,and ACC, which are involved in lipogenesis. Similar to previousreports,11,13,25,26 mRNA expression levels of these moleculeswere increased in the kidneys of PPAR-+/+ mice during 4 wk ofHFD, whereas these were not observed in the kidneys of insulin-sensitivePPAR-+/– mice. Therefore, we can show that the increasein renal lipogenesis is observed from the early stage of HFD,before neutral lipid accumulation in the kidney. These observationsprovide further evidence that the accelerated renal lipogenesiscontributes to the development of renal lipid accumulation underinsulin resistance.
In addition to renal lipogenesis, we examined the effects ofHFD on renal lipolysis to determine its role in the developmentof renal lipid accumulation. Our results showed that mRNA expressionlevels of CPT-1, which is one of the key enzymes involved inlipolysis, were significantly decreased during the 4 wk of HFDbut not in PPAR-+/– mice. These results suggest that renallipolysis decreases under insulin resistance, which may contributeto renal lipid accumulation. PPAR- also regulates lipolysisin various tissues.27 However, we failed to find significantdifferences of renal mRNA expression levels of PPAR- among thefour groups. Furthermore, we could not observe differences ofrenal mRNA expression of ACO and MCAD, which are transcriptionaltarget molecules of PPAR-. These results suggest that HFD mightnot affect mRNA expression of PPAR- or activity of PPAR- inthis mouse model of metabolic syndrome.
In this study, we found decreased renal mRNA expression levelsof CPT-1, although those of ACO, MCAD, and PPAR- were not changed,in PPAR-+/+ mice on an HFD. We therefore focused on the activityof the AMPK pathway to explore this discrepancy, because thispathway is a key regulator of intracellular lipid metabolismin other tissues23 and because activated AMPK inactivates ACC,resulting in a decrease in malonyl-CoA, with subsequent releaseof inhibition of CPT-1 expression levels and acceleration oflipolysis.23 Under an HFD, phosphorylation of AMPK(Thr172) andACC(Ser79) was significantly decreased in the kidneys of PPAR-+/+mice but not in the kidneys of PPAR-+/– mice. These resultssuggest that decreased AMPK activity in the kidney under anHFD could increase the activity of ACC and intracellular malonyl-CoAcontent, resulting in the decreases in renal mRNA expressionof CPT-1. These results could provide new evidence that a decreasein lipolysis via inhibiting the AMPK–CPT-1 pathway butnot PPAR- could contribute to renal lipid accumulation underan HFD. Furthermore, these results suggest that posttranslationalactivation of ACC by inhibiting AMPK activity under an HFD mightcontribute to the acceleration of renal lipogenesis, as wellas increased renal expression of ACC.
In this study, we show that the improvements of systemic metabolicabnormalities result in the attenuation of HFD-induced renallipid accumulation and renal injury with the improvement ofrenal lipid metabolism in PPAR-+/– mice. We previouslyreported that moderate reduction of PPAR- activity could decreaselocal lipid accumulation in the liver and skeletal muscle inPPAR-+/– mice.20 These results raise the question of whetherthe reduction of PPAR- activity could directly affect the improvementof renal lipid metabolism in the kidneys of PPAR-+/– miceon an HFD. Liver-specific PPAR- disruption could attenuate steatohepatitiswith the reduction of lipid accumulation in leptin-deficientmice.28 Also, deletion of PPAR- in adipose tissues of mice protectsagainst HFD-induced adipocyte hypertrophy, which inhibits obesityand insulin resistance.29 These reports suggest that a reductionof PPAR- activity may inhibit various diseases that are associatedwith local lipid accumulation in various peripheral tissues,including kidney. However, our study does not provide enoughevidence to clarify whether PPAR- deficiency in the kidney directlyregulates renal lipid metabolism, as well as other peripheraltissues.28,29 Further studies are required to determine thedirect effects of PPAR- activity on renal lipid metabolism.
Several investigators have reported that PPAR- agonists canprotect against the various types of renal injury through theiranti-inflammatory and antifibrotic effects.30–32 In contrast,our results showed that systemic reduction of PPAR- expressioncould improve HFD-induced renal injury. We therefore suggestthat both PPAR- agonists and PPAR- insufficiency in the absenceof ligands can protect against renal injury that is associatedwith glucose and lipid metabolism abnormalities, at least inpart, through the attenuation of both systemic and renal lipidmetabolism. Furthermore, several reports show that PPAR- recruitsother transcriptional co-repressor complexes in the absenceof ligand and that these co-repressors are capable of downregulatingPPAR-–mediated transcriptional activity.33,34 This mightbe another mechanism through which both ligand binding to PPAR-and ligand-free PPAR- deficiency could promote renal protection.
Here, we present evidence that HFD causes renal lipid accumulationand renal injury with increased renal lipogenesis and decreasedrenal lipolysis, whereas these abnormalities are attenuatedin insulin-sensitive PPAR-+/– mice. These results suggestthat the improvement of an imbalance between renal lipogenesisand lipolysis results in a reduction of renal lipid accumulationand subsequent attenuation of renal injury under insulin resistance.Therefore, we propose that attenuation of renal lipid metabolismcould serve as a new therapeutic strategy to prevent the developmentof CKD in metabolic syndrome.
Animal Models PPAR-+/– mice were generated as described previously.21Six-week-old mice were housed in box cages, maintained on a12-h light/12-h dark cycle, and fed an LFD (10% of kilocaloriesfrom fat) or HFD (45% of kilocalories from fat) obtained fromResearch Diets (New Brunswick, NJ) for 16 wk. At the end of16-wk period, body weight, BP, and blood glucose were measured.BP of conscious mice was measured at a steady state with a programmabletail-cuff sphygmomanometer (BP98-A; Softron, Tokyo, Japan).Mice were placed in metabolic balance cages for 24-h urine collectionto measure albumin concentration. Mice were anesthetized andperfused as described previously.11 The right kidney was embeddedin paraffin for PAS staining and immunohistochemistry or wasfrozen for Oil-Red O staining. Total RNA and protein were extractedfrom the remaining renal cortex of the left kidney. The ResearchCenter for Animal Life Science of Shiga University of MedicalScience approved all experiments.
Antibodies
Anti–phospho-acetyl CoA carboxylase(Ser79) was obtainedfrom Upstate Cell Signaling (Lake Placid, NY). Anti–phospho-AMPK(Thr172),anti-AMPK(23A3), and anti-ACC were from Cell Signaling Technology(Beverly, MA).
Blood and Urine Analysis
Cholesterol or triglycerides were measured using the cholesterolCII kit or L type TG H kit (Wako Chemicals, Richmond, VA). Plasmainsulin was determined using an ELISA (Exocell, Philadelphia,PA). Plasma leptin, MCP-1, and TNF- were assayed with the immunoassaykit (R&D Systems, Minneapolis, MN). Plasma adiponectin wasdetermined with a mouse-specific ELISA kit (Linco Research,St. Charles, MO). Urinary albumin excretion was measured witha mouse-specific sandwich ELISA system (Albuwell; Exocell) andwas expressed as total amount excreted in 24 h.
Protein Extraction and Western Blot Analysis
The renal cortex was homogenized in an ice-cold lysis buffercontaining 150 mmol/L NaCl, 50 mmol/L Tris-HCl (pH 8.0), 0.1%SDS, 1% Nonidet P-40, and protease inhibitor cocktail (BoehringerMannheim, Lewes, UK). These samples were resolved by 10% SDS-PAGEand transferred to polyvinylidene fluoride membranes (Immobilon,Bedford, MA). The membranes were incubated with the appropriateantibodies, washed, and incubated with horseradish peroxidase–coupledsecondary antibodies (Amersham, Buckinghamshire, UK). The blotswere visualized by using an enhanced chemiluminescence detectionsystem (Perkin Elmer Life Science, Boston, MA).
RNA Extraction and Quantitative Real-Time PCR
Total RNA was isolated from the renal cortex based on the TRIzolprotocol (Invitrogen Life Technologies, Carlsbad, CA). cDNAwas synthesized using reverse transcript reagents (Takara, Otsu,Japan). iQSYBR Green Supermix (Bio-Rad Laboratories, Hercules,CA) was used for real-time PCR (ABI Prism TM 7500 Sequence DetectionSystem; Perkin-Elmer Applied Biosystems). The levels of mRNAexpression of these molecules were quantified using standardcurve method. Standard curves were constructed using seriallydiluted standard template. Ct value was used to compute thelevels of mRNA expression from the standard curve. Analyticaldata were adjusted with the levels of mRNA expression of -actinas an internal control. Primers used are described in Table 4.
Lipid Extraction and Analysis
Total lipid was extracted from the renal cortex by the methodof Bligh and Dyer.35 Triglyceride and cholesterol contents weredetermined as described previously.
Morphologic Analysis
Fixed kidneys were embedded in paraffin, sectioned (3-µmthick), and then stained with PAS reagent as described previously.36From each mouse, 20 glomeruli cut at their vascular poles wereused for morphometric analysis. The extent of the mesangialmatrix (defined as mesangial area) was determined by assessmentof the PAS-positive and nucleus-free area in the mesangium usinga computer-assisted color image analyzer (LUZEX F; Nikon, Tokyo,Japan). Immunohistochemical staining was performed with fibronectin-specificpolyclonal anti-mouse antibody (A852/R5H; Biogenesis, Poole,UK). For evaluation of immunostaining for fibronectin, the percentagesof area stained for fibronectin were graded as follows: 0, stainingabsent to 5%; 1, 5 to 25%; 2, 25 to 50%; 3, 50 to 75%; and 4,>75%.36 An investigator who was masked to sample identityperformed the image analysis. Frozen sections were used forOil-Red O staining, as previously reported.11
Glucose Tolerance Test and Insulin Tolerance Test
For glucose tolerance tests, mice were fasted overnight for14 h followed by intraperitoneal glucose injection (1 g/kg bodywt). Blood glucose was measured using tail blood collected at0, 15, 30, 60, and 120 min after the injection.37 For insulintolerance tests, mice were administered an injection of humanregular insulin (Novolin R; Novo Nordisk, Clayton, NC) at 0.75U/kg body wt intraperitoneally after a 6-h fast, and blood glucosewas measured at 0, 15, 30, and 60 min.37
Statistical Analyses
Results are expressed as means ± SEM. ANOVA with subsequentScheffe test was used to determine the significance of differencesin multiple comparisons. P < 0.05 was considered statisticallysignificant.
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Abstract
Introduction
–deficient (PPAR
and monocyte chemoattractant protein-1 (MCP-1) levels, compared with their counterparts on an LFD. Plasma adiponectin levels in PPAR-
-actin as an internal control. Primers used are described in Table 4. 
