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Endocrinology Vol. 147, No. 1 44-50
Copyright © 2006 by The Endocrine Society

Obesity-Related Glomerulopathy: Insights from Gene Expression Profiles of the Glomeruli Derived from Renal Biopsy Samples

Yichao Wu, Zhihong Liu, Zhaoying Xiang, Caihong Zeng, Zhaohong Chen, Xiaojing Ma and Leishi Li

Research Institute of Nephrology (Y.W., Z.L., C.Z., Z.C., L.L.), Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China; and Department of Microbiology and Immunology (Z.X., X.M.), Weill Medical College of Cornell University, New York, New York 10021

Address all correspondence and requests for reprints to: Zhihong Liu, M.D. Professor of Medicine, Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China. E-mail: zhihong{at}21cn.net.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Obesity-related glomerulopathy (ORG) is an important complication of obesity. The pathophysiological mechanism of glomerular injury in ORG is incompletely understood. Gene expression profiles in the glomeruli obtained from renal biopsy samples of patients with ORG were investigated, using a microdissection technique combined with Affymetrix microarray analysis. Six patients presented with obesity, proteinuria, and biopsy-proven ORG were enrolled. Two sex- and age-matched donor kidneys were applied as the controls. Glomeruli were dissected out from renal biopsy samples under microscope, and total RNA was extracted using RNeasy Micro kit. After two rounds of T7 promoter-based RNA amplification, gene expression profiles of the glomeruli samples were detected using Affymetrix U133A gene chips. Bioinformatic tools were applied to analyze the microarray data. Results of candidate ORG-related genes were further confirmed by real-time quantitative PCR and immunohistochemistry staining using renal biopsy samples of a larger pool of 15 ORG patients. Genes related to lipid metabolism, inflammatory cytokines, and insulin resistance were the most highlighted subgroups that significantly changed in the glomerular gene expression profiles of the ORG patients, compared with the controls. The expression levels of several key genes in lipid metabolism were increased over 2-fold, including low-density lipoprotein receptor, fatty acid binding protein 3, and sterol regulatory element binding protein 1. Moreover, some inflammatory cytokines and their downstream molecules were increased as well, including TNF-{alpha} and its receptors, IL-6 signal transducer, and interferon-{gamma}. As the indicators of insulin resistance in the local glomerular cells, levels of glucose-transporter 1, leptin receptor, peroxisome proliferator-activated receptor-{gamma}, and vascular endothelial growth factor increased, too. In addition to lipid dysmetabolism and insulin resistance, the activation of an inflammatory process in the glomeruli might play a unique role in the development of obesity-related glomerulopathy. Our results expand the understanding of obesity-induced glomerular injuries and shed light on new approaches in the treatment of this disease.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE PREVALENCE OF obesity all over the world has been steadily rising in the past two decades, a trend that has been linked to increases in dietary intake, especially fat intake, and a sedentary lifestyle (1, 2). It is well documented that obese patients are at greater risks to develop sleep apnea, hyperlipidemia, hypertension, coronary vascular disease, insulin resistance, and diabetes, and more attention has been paid to the impact of obesity on renal functions recently (3, 4, 5). The relationship between massive obesity and nephritic-range proteinuria was first reported in 1974 (6). After that, increased evidence demonstrated that obesity-related glomerulopathy (ORG) should be identified as an isolated complication of obesity (7, 8, 9).

From clinical and histological features of ORG patients, it was estimated that the renal effects of obesity include both structural and functional adaptations, such as glomerular hyperfiltration, increased accumulation of extracellular matrix, and renal hypertrophy (10, 11). Most obese patients suffered from insulin resistance syndrome (X syndrome), presenting with increased free fatty acid, hyperinsulinemia, dyslipidemia, hyper uric acid, and abnormal levels of steroid in the peripheral circulation (12). Therefore, these elements have been estimated to play important roles in causing renal lesions. However, the underlying mechanism of the development of ORG still remains unclear.

Conventional research tools have restricted investigators to focus on single genes or isolated pathways in separate studies. Microarray analysis provides the opportunity for evaluating the involved factors at a genomic scale (13). To obtain complementary information that allows a stringent insight into the pathogenesis of ORG, gene expression profiles of the glomeruli of patients with ORG were investigated in the present study. Glomeruli were collected directly from renal biopsy samples of patients with ORG, using the microdissection technique under microscope (14, 15). Sex- and age-matched donor kidney samples were applied as the controls. Gene expression profiles were detected using Affymetrix U133A GeneChips and analyzed by bioinformatic tools. Furthermore, the results of microarray analysis were confirmed in a larger pool of patients using real-time PCR and immunohistochemistry staining.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient information
The World Health Organization’s definitions of overweight and obesity are based on increased value of body mass index (BMI) as well as morbidity risks (16). Six patients (from ORG-1 to ORG-6) who presented with obesity (BMI > 30 kg/m2), proteinuria, and biopsy-proven ORG were enrolled in the present study. The histological changes in renal biopsy sections of these patients were defined as obesity-associated focal segmental glomerulosclerosis with glomerulomegaly or as obesity-associated glomerulomegaly alone (9). Patients with other underlying conditions that could cause secondary focal segmental glomerulosclerosis or glomerulomegaly were carefully excluded. There was no obvious difference in the clinical manifestations and medications of these six patients. Two sex- and age-matched donor kidneys were applied as the controls. The donors had no history of hypertension, obesity, diabetes, and renal diseases, and their serum creatinine levels were in the normal range. Pathological morphology of the donor kidneys was normal under light microscopic examination. The clinical characteristics of these ORG patients are shown in Table 1Go. Fifteen more patients with ORG (from ORG-1' to ORG-15') were selected as a larger pool of patients for further confirmation of the microarray results, compared with five more control kidneys (from control-1' to control-5'). These 15 patients also presented with obesity (BMI > 30 kg/m2), overt proteinuria (2.08–3.97 g/24 h), and biopsy-proven ORG. There was no obvious difference in the clinical manifestations of these patients compared with those six patients enrolled in the previous microarray analysis. As for medical treatment, some of the patients in this larger pool had not been treated with angiotensin-converting enzyme inhibitor (ACEI) when their renal biopsies were performed (see Table 5Go). Clinical information and medical treatment about this larger pool has been provided as additional information. Informed consent was obtained from all the patients to use their tissue samples and clinical information for research purposes. Approval for the use of human subjects had been acquired from the relevant research advisory committee in the university.


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  		TABLE 1. Clinical parameters of the patients and the controls

 

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  		TABLE 5. Semiquantitative immunostaining of VEGF, GLUT1, and TNF-{alpha} in the glomeruli of 15 patients with ORG compared with five controls

 
Renal biopsy and sample preparation
Percutaneous renal biopsies were performed in each patient under ultrasonographic guidance. Three cores of renal tissues were obtained. Two of them were preserved for pathological diagnosis, and the left one was instantly used for glomeruli microdissection. Bowman’s capsules were stripped away by sterile microforceps, and 15–20 glomeruli were dissected out from each sample under a microscope (14, 15). After washing in PBS, the isolated glomeruli were immediately put in RLT solution provided by the RNeasy Micro kit (QIAGEN, Valencia, CA) and kept in liquid nitrogen for further extraction of total RNA.

Gene expression profiling with Affymetrix U133A arrays
Total RNA was extracted from each sample of glomeruli using RNeasy Micro kit. Approximately 30–50 ng total RNA was extracted from each sample. After two rounds of T7 promoter-based RNA linear amplification in vitro, each sample typically provided a final yield of 20–50 µg amplified mRNA, which is enough for subsequent microarray analysis. Hybridization, washing, and staining with human genome U133A arrays were carried out in an Affymetrix hybridization oven and the Fluidics Station (Affymetrix, Santa Clara, CA) (17). The U133A array contains approximately 14,500 well substantiated genes and has been successfully applied in gene expression profiling of various human diseases (18, 19). After proper washing procedures, the GeneChips were scanned by a Hewlett Packard confocal laser scanner and visualized using the Affymetrix GeneChip 5.0 software.

Data collection and analysis
Data normalization, log transformation, statistical analysis, and pattern study were performed with the GeneSpring software (Silicon Genetics, Redwood City, CA) (20). We normalized the raw data by using per-chip and per-gene, two steps of global normalization method to scale the expression levels around 1. We also performed logarithm transformation of the normalized data, which yielded more symmetric data for further parametric statistical analysis. Welch t test, a parametric test assuming unequal variances, was then applied to carry through statistical comparison between the ORG patients and the controls. P value, the probability of a false positive, was set to less than 0.01. A two-way hierarchical clustering by distance measure was used to analyze genes that were differentially expressed between the two groups. The standard correlation was chosen to measure the similarity, and the minimum distance to separate genes or samples was 0.001. Finally, through the NetAffx analysis center online (www.affymetrix.com), biological roles of the significantly varied genes in the glomerular gene expression profiles were annotated (21).

Confirmation of microarray results
To validate the findings of gene transcription levels measured by microarray analysis, the expression of several candidate genes [low-density lipoprotein (LDL) receptor, TNF-{alpha}, vascular endothelial growth factor (VEGF), TGF-ß1, glucose transporter (GLUT)-1, and leptin receptor] were checked in the glomeruli of the six ORG patients and two controls by real-time quantitative PCR (22). Oligonucleotide primers and probes (Applied Biosystems, Foster City, CA) were cDNA specific, not amplifying genomic DNA. Quantification of the given templates was performed according to the standard curve method. Serial dilutions of standard cDNA from a human nephrectomy sample were included in all PCR runs and served as standard curve. Controls consisting of bi-distilled H2O were negative in all runs. Relative expression levels of the six gene transcripts were normalized for the mRNA expression level of human glyceraldehyde-3-phosphate-dehydrogenase (GAPDH). The relative expression levels of these genes in controls were set to 1. Furthermore, glomeruli obtained from renal biopsy samples of 15 more ORG patients were applied to confirm the variation of LDL receptor, TNF-{alpha}, VEGF, and leptin receptor, compared with a panel of five more of donor kidney samples. Sequences of the TaqMan primers and probes are shown in Table 2Go.


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  		TABLE 2. Primer and TaqMan probe sequences

 
To further confirm the variation of TNF-{alpha}, GLUT1, and VEGF expression at the protein level, semiquantitative immunohistochemistry was performed on renal biopsy sections of that larger pool of 15 ORG patients and five controls using specific antibodies. Frozen renal biopsy sections were fixed in precooled acetone, and nonspecific binding sites were blocked off by normal rabbit serum. The sections were then incubated with goat antihuman TNF-{alpha} antibody (1:100) (R&D Systems, Minneapolis, MN) and rabbit antihuman GLUT1 antibody (1:100) (Chemicon, Pittsburgh, PA) overnight at 4 C, respectively. Fluorescein-conjugated rabbit antigoat IgG and swine antirabbit IgG were applied for 45 min after PBS washing. The sections were then observed under fluorescent microscope. As for immunohistochemistry staining of VEGF, renal biopsy samples were fixed in 10% neutral buffered formaldehyde and processed for paraffin embedding. Endogenous peroxidase in the tissue sections was blocked with 0.3% hydrogen peroxide. For antigen retrieval, the sections were subject to microwave treatment using 0.15 M Tris-HCl buffer (pH 8.2) and then were incubated with monoclonal antihuman VEGF antibody (Abcam, Cambridge, UK) at 4 C overnight. Horseradish peroxidase-conjugated rabbit antimouse IgG, swine antirabbit IgG, and a complex of rabbit peroxidase-antiperoxidase antibody (Dakocytomation, Glostrup, Denmark) were applied sequentially, each for 45 min. The sections were visualized using 3'-diaminobenzidine. After counterstaining with hematoxylin, the sections were further dehydrated and mounted for scoring. For semiquantitative analysis, scoring of glomerular immunostaining using the system of –, ±, +, and 2+ was performed on 15 cortical glomerular sections in each subject at an original magnification of x400 by an independent pathologist. Data were presented as means ± SE and analyzed by one-way ANOVA.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Compared with the controls from donor kidneys, there were 256 genes changed significantly in the glomeruli obtained from renal biopsy samples of patients with ORG (P < 0.01). The top candidate genes with increased or decreased expression levels are shown in Tables 3Go and 4Go.


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  		TABLE 3. The top increased genes in the glomeruli of ORG patients compared with controls (>2-fold; P < 0.01)

 

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  		TABLE 4. The top decreased genes in the glomeruli of ORG patients compared with controls (>2-fold; P < 0.01)

 
Distinct up-regulation of genes related to inflammatory cytokines
Hierarchical clustering was used to visualize the coordinated expression profiles of the 256 genes over eight glomerular samples, as shown in Fig 1Go. It was found that the global expression trends of these genes in all of the ORG samples were similar, which was distinctly different from those in the controls. Meanwhile, there was a high degree of similarity in gene expression profiles of the two controls.



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  		FIG. 1. Hierarchical clustering analysis of the 256 genes (displayed vertically) significantly changed in ORG patients (P < 0.01). The total 256 genes were clustered based on their expression patterns among the eight glomerular samples (displayed horizontally). Red indicates up-regulated genes; down-regulated genes are shown in blue; and yellow means an average level across the eight glomerular samples.

 
Interestingly, there was a distinctive up-regulation of genes related to inflammatory cytokines in the glomeruli of ORG patients (Table 3Go). The expression levels of TNF-{alpha} and its receptors, IL-6 signal transducer, granulocyte-macrophage colony-stimulating factor 2 (GM-CSF2) and interferon-{gamma} increase obviously in the glomeruli derived from ORG patients.

Genes related to lipid metabolism and insulin resistance
Functional annotation showed that there was a high similarity in expression patterns of genes involved in lipid metabolism and insulin resistance in the glomeruli of patients with ORG. Particularly, significant up-regulation of LDL receptor, fatty acid binding protein 3, and sterol regulatory element binding protein 1 (SREBP-1) were observed. Besides, there was also up-regulation in several genes related to extracellular matrix modulation, as shown in Table 3Go. We take great interest in the abnormal regulation of LDL receptor, TNF-{alpha}, VEGF, TGF-ß1, GLUT1, and leptin receptor and selected them as candidate ORG-related genes for future research.

Confirmation of the candidate genes in a larger pool of patients
Using real-time quantitative PCR, we confirmed that the expression levels of six candidate genes increased significantly in the six glomeruli samples of ORG patients, compared with the two controls (Fig. 2Go). For each of the six candidate genes (LDL receptor, TNF-{alpha}, VEGF, TGF-ß1, GLUT1, and leptin receptor), relative mRNA expression levels quantified by real-time PCR were similar in trend to those of the microarray assessment. Significantly increased mRNA levels of LDL receptor, TNF-{alpha}, VEGF, and leptin receptor were also verified in the larger pool of 15 ORG patients, compared with five more controls (P < 0.05).



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  		FIG. 2. Confirmation of microarray data of gene expression in the glomeruli of ORG patients by real-time PCR. A, Average mRNA levels of LDL receptor, TNF-{alpha}, VEGF, TGF-ß1, GLUT1 and leptin receptor in the glomeruli of the ORG patients and the controls enrolled in this study; B, average mRNA levels of LDL receptor, VEGF, leptin receptor, and TNF-{alpha} measured by real-time PCR in the glomeruli of a larger pool of 15 patients with ORG, compared with a panel of five more control kidneys. The real-time PCR data have been normalized for the level of human GAPDH. *, P < 0.01; #, P < 0.001 compared with controls (one-way ANOVA).

 
In addition, the alterations of TNF-{alpha}, GLUT1, and VEGF expression in the glomerular samples of that larger pool of ORG patients were investigated using immunohistochemical staining. In control renal tissues, TNF-{alpha}, GLUT1, and VEGF showed trace staining in the glomeruli. Renal biopsy samples from this larger pool of 15 ORG patients showed that the staining signals for VEGF were much stronger in the glomeruli of patients as compared with controls. The staining signals of TNF-{alpha} and GLUT1 were also increased moderately in the glomeruli of patients with ORG (Fig. 3Go). Using a semiquantitative system, it was found that there were significant changes in the expression of VEGF (P < 0.05), GLUT1 (P < 0.05), and TNF-{alpha} (P < 0.01), compared between the patients and the controls (Table 5Go).



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  		FIG. 3. The distribution of VEGF, TNF-{alpha}, and GLUT1 in the glomeruli of ORG patients and controls by immunohistochemistry staining. A, C, and E, A typical distribution of VEGF, TNF-{alpha}, and GLUT1 in the glomeruli of controls, respectively (n = 5); B, D, F, a typical distribution of VEGF, TNF-{alpha}, and GLUT1 in the glomeruli of ORG (n = 15). Original magnification, x400.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The gene expression profile of glomeruli derived directly from renal biopsy samples of patients with ORG was investigated in the present study. By means of bioinformatic tools, it was found that there were 256 genes that varied significantly in the patients with ORG compared with the controls from donor kidneys. Impressively, genes related to inflammatory cytokines, lipid metabolism, and insulin resistance were the most highlighted subgroups to be regulated in the glomeruli of patients with ORG.

Interestingly, there was a distinct up-regulation of inflammatory cytokines and their related molecules in the glomeruli of ORG patients, including TNF-{alpha} and its receptors, IL-6 signal transducer, and interferon-{gamma}. Using real-time PCR and immunohistochemistry staining, the microarray results were further confirmed in a larger pool of patients. Obviously, there was an increased expression of TNF-{alpha} in the glomeruli of ORG patients, which has been shown to be a key inflammatory factor leading to insulin resistance (23). Meanwhile, the expression levels of interferon-{gamma} and GM-CSF2 were confirmed to increase significantly, also indicating that there might be active inflammatory responses in the glomeruli of patients with ORG (24, 25). Furthermore, the expression of IL-6 signal transducer (one component of IL-6 receptor located in the cell membrane) also up-regulated obviously. It has not been documented how the inflammatory process would influence the physiology of local glomerular cells in obese patients. Circulating levels of TNF-{alpha} are very low compared with tissue levels (26), and in the present study, glomeruli contained not only elevated protein levels of TNF-{alpha} but also elevated TNF-{alpha} mRNA. Therefore, data from the present study indicated that TNF-{alpha} is an important factor involved in the development of ORG. Meanwhile, it also implies that glomerular cells themselves could act as active responders to the abnormal ambience of elevated levels of inflammatory factors, thus accelerating the process of glomerular injury.

Besides inflammatory cytokines, the role of other cytokines, especially VEGF, should also be emphasized in the development of ORG deduced from our data. Our previous work demonstrated that the overexpression of VEGF and its receptor VEGF-R2 was strongly associated with the development of glomerular endothelial lesions (27). The present study demonstrated that VEGF might play an important role in the development of pathological changes in ORG patients, especially the formation of glomerular hypertrophy.

It was also demonstrated that genes related to lipid dysmetabolism were one of the subgroups changed significantly in the glomerular gene expression profiles of ORG patients. Hyperlipidemia could lead to insulin resistance and is highly associated with renal damage (28). Our data showed that the expression levels of LDL receptor, SREBP-1, and fatty acid binding protein 3 all increased significantly in the glomeruli of patients with ORG. In addition, IGF-I was also found to be up-regulated. The simultaneous up-regulation of SREBP-1 and LDL receptor observed in the ORG patients was rational because SREBP-1 has been reported to be selectively involved in the signal transduction pathway of insulin and IGF-I, which leads to the activation of LDL receptor gene (29). Therefore, this result also illustrated a close relationship between renal lipotoxicity and local insulin resistance in the pathogenesis of ORG.

Expression levels of genes involved in insulin signaling and glucose metabolism showed obvious alterations in ORG patients. The expression of GLUT1, peroxisome proliferator-activated receptor-{gamma}, and leptin receptor all increased in the glomeruli samples of ORG patients. Previously, we have revealed that the up-regulation of GLUT1 in renal resident cells, especially in mesangial cells, is critical in causing insulin resistance and glucose dysmetabolism in the kidney of patients with diabetic nephropathy (30, 31). The broad up-regulation of genes with relationship to insulin resistance in the present study indicates that local insulin resistance should be involved in the development of glomerular lesions in patients with ORG. Meanwhile, the potential role of leptin in the pathogenesis of ORG has also been noticed with great interest. As a small peptide hormone that is mainly produced in adipose tissues, leptin has seldom been reported to have direct pathological effects on renal resident cells. It was reported in vitro that leptin could stimulate cellular proliferation, TGF-ß1 synthesis, and type IV collagen production (32). Our data showed an obvious up-regulation of leptin receptor in the glomeruli of ORG patients, and it offers direct evidence of possible involvement of leptin in the cellular dysfunction in the glomeruli of patients with ORG.

Although several pieces of studies using microarray to analyze gene expression profiles in renal diseases have been reported (33, 34), tissues obtained directly from renal biopsy samples of the clinical patients have not been reported yet. Meanwhile, a major limitation for studies of renal disease at the molecular level is the heterogeneity of the kidney, which contains different proportions of glomeruli and tubular segments. In this study, glomeruli were microdissected out from renal biopsy samples of patients, which partly reduced such heterogeneity and enabled us to focus on the glomeruli where the main pathological changes of ORG are located. The number of controls in the microarray analysis was limited in our study, which might contribute to some deviation of the changes in gene expression profiles. Meanwhile, the treatment of ACEI in some of the ORG patients but not in the controls might have influenced the results as well. However, through clustering analysis there was a high degree of similarity in gene expression profiles of the two controls from donor kidneys. And more importantly, the results deduced from microarray analysis were quite reproducible through confirmation in a larger pool of ORG patients by real-time quantitative PCR and immunohistochemistry studies, which substantiated our findings to some extent. Another doubt may exist in the design of controls for this study. In other organs, proteinuria itself could modify the gene and protein expression, particularly in the liver (35). However, as for the kidney itself, proteinuria is usually one of the main results, as well as an accelerating factor in various renal diseases. Nonobese subjects with proteinuria caused by other kinds of etiology, including different kinds of primary glomerulonephritis or secondary nephropathy, are a very complicated collection themselves. The changes in gene expressions profiles influenced by proteinuria per se could not be separated from those other pathogenic factors. And the gene expression profiles in nonobese proteinuric subjects would mainly reflect a global result caused by all the pathogenic factors. Therefore, similarly proteinuric subjects, albeit not obese, might not serve as an ideal control for this study.

The current study demonstrated for the first time that inflammatory cytokines and related downstream pathways play a unique role in the formation of obesity-related glomerular injuries. Meanwhile, VEGF also participates in the pathogenesis of ORG. It has also demonstrated that some important dysmetabolism caused by obesity, such as lipid dysmetabolism and insulin resistance, are involved in the development of ORG. These findings provide important clues for the further understanding and treatment of obesity-associated organ lesions. With the enormous advances in the field of functional genomics, and coupled with the high-throughput techniques applied in the study of renal biopsy samples, it is certainly the time to move on and open more effective approaches for the research of obesity-related organ damage.


   Footnotes
 
First Published Online October 6, 2005

Abbreviations: ACEI, Angiotensin-converting enzyme inhibitor; BMI, body mass index; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GLUT, glucose transporter; GM-CSF2, granulocyte-macrophage colony-stimulating factor 2; LDL, low-density lipoprotein; ORG, obesity-related glomerulopathy; SREBP, sterol regulatory element binding protein; VEGF, vascular endothelial growth factor.

Received May 31, 2005.

Accepted for publication September 26, 2005.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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