AJP - Renal Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Renal Physiol 289: F1153-F1158, 2005. First published May 10, 2005; doi:10.1152/ajprenal.00097.2005
0363-6127/05 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
289/5/F1153    most recent
00097.2005v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (17)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Panchapakesan, U.
Right arrow Articles by Chen, X.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Panchapakesan, U.
Right arrow Articles by Chen, X.

PPAR{gamma} agonists exert antifibrotic effects in renal tubular cells exposed to high glucose

U. Panchapakesan, S. Sumual, C. A. Pollock, and X. Chen

Department of Medicine, University of Sydney, and Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, New South Wales, Australia

Submitted 10 March 2005 ; accepted in final form 1 May 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) are ligand-activated transcription factors that regulate cell growth, inflammation, lipid metabolism, and insulin sensitivity. We recently demonstrated that PPAR{gamma} agonists limit high glucose-induced inflammation in a model of proximal tubular cells (PTC; Panchapakesan U, Pollock CA, and Chen XM. Am J Physiol Renal Physiol 287: F528–F534, 2004). However, the role of PPAR{gamma} in the excess extracellular matrix production is largely unknown. We evaluated the effect of 24- to 48-h 8 µM L-805645 or 10 µM pioglitazone on 25 mM D-glucose-induced markers of fibrosis in HK-2 cells. High D-glucose induced nuclear binding of activator protein-1 (AP-1) to 140.8 ± 10.9% (P < 0.05), which was attenuated with L-805645 and pioglitazone to 82.3 ± 14.4 (P < 0.01 vs. high D-glucose) and 99.3 ± 12.2% (P < 0.05 vs. high D-glucose), respectively. High D-glucose increased total production of transforming growth factor (TGF)-{beta}1 139.6 ± 6.5% (P < 0.05), which was reversed with L-805645 and pioglitazone to 68.73 ± 5.7 (P < 0.01 vs. high D-glucose) and 112 ± 13.6% (P < 0.05 vs. high D-glucose). L-805645 and pioglitazone reduced high D-glucose-induced fibronectin from 156.0 ± 24.9 (P < 0.05) to 81.9 ± 16.0 and 57.4 ± 12.7%, respectively (both P < 0.01 vs. high D-glucose). Collagen IV was not induced by high D-glucose. L-805645 and pioglitazone suppressed collagen IV to 68.0 ± 14.5 (P < 0.05) and 46.5 ± 11.6% (P < 0.01) vs. high D-glucose, respectively. High D-glucose increased the nuclear binding of NF-{kappa}B to 167 ± 22.4% (P < 0.05), which was not modified with PPAR{gamma} agonists. In conclusion, PPAR{gamma} agonists exert antifibrotic effects in human PTC in high glucose by attenuating the increase in AP-1, TGF-{beta}1, and the downstream production of the extracellular matrix protein fibronectin.

thiazolidinediones; diabetic nephropathy; proximal tubular cells

DIABETES MELLITUS (DM) IS a major global health issue with up to one-third of patients suffering end-stage renal disease. The major burden of disease is derived from patients with type 2 DM (25), resulting in up to 50% of adult patients on dialysis in Westernized countries having diabetic nephropathy as their primary diagnosis.

The interventions shown to prevent the onset or attenuate the progression of diabetic nephropathy include glycemic and blood pressure control (10, 32), specific interruption of the renin-angiotensin system with either angiotensin-converting enzyme inhibitors (30) or angiotensin II receptor blockers (6, 20) and potentially lipid-lowering therapy (3, 9). Understanding the mechanisms underlying the development of diabetic nephropathy is essential in establishing novel therapeutic strategies for the prevention or arrest of progressive renal failure. The search for specific molecular targets is ongoing, and PPAR{gamma} agonists may show promise.

PPAR{gamma} are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that have a central role in regulating insulin sensitivity, adipocyte differentiation, cell growth, and inflammation (13). Synthetic agonists of PPAR{gamma} like the thiazolidinediones (TZDs) are widely used as insulin-sensitizing agents in patients with type 2 DM. On ligand binding, PPAR{gamma} form heterodimers with the retinoic acid receptor (23). This complex then binds to the PPAR response elements (PPREs) within the promoter region of target genes. Regulation of these target genes depends on the binding of ligands as well as complex interaction between resident coactivators and corepressors (36). Endogenous ligands include 15-deoxy-{Delta}12,14-prostaglandin J2 (11, 17) and metabolites of oxidized low-density lipoproteins (LDL) (24, 31). Synthetic ligands include the TZDs and phenylacetic acid derivatives such as L-805645, which are specific, and selective PPAR{gamma} ligands (5).

There are several clinical studies demonstrating a beneficial trend, with a reduction in albuminuria in patients with type 2 DM treated with TZDs (5, 15, 18). This finding is also reflected in animal models of experimental diabetic nephropathy where treatment with TZDs reduces albuminuria and decreases glomerular matrix deposition and glomerulosclerosis (7, 8, 22, 39). These benefits appear to be independent of glycemic control. Haplo-insuffficient PPAR+/– db/db mice exhibit more severe hyperglycemia, albuminuria, and glomerular pathology (39). The renoprotective benefit of PPAR{gamma} agonists is further suggested by studies in nondiabetic models of renal injury, such as the 5/6-nephrectomy model, where activation of PPAR{gamma} reduced glomerulosclerosis (21). In vitro studies have focused on the use of mesangial cells where PPAR{gamma} has been well characterized (2, 26), with specific PPAR{gamma} activation exerting an antiproliferative (12, 26) and antifibrotic effect, reducing type 1 collagen synthesis and secretion (29) presumed due to a transforming growth factor (TGF)-{beta}1-dependent mechanism (34). In mesangial cells, pioglitazone has been shown to inhibit TGF-{beta}-induced fibronectin production (14). In our own study using an immortalized proximal tubular cell model (opossum kidney cell line) under normal (5 mM)-glucose conditions, we have previously demonstrated that PPAR{gamma} agonists stimulate tubular albumin uptake without provoking an inflammatory response (37). However, whether they protect the kidney from tubulointerstitial fibrosis, the hallmark of a progressive decline in renal function under hyperglycemic conditions, is unknown. Thickening of the basement membrane due to an increase in extracellular matrix production by renal proximal tubular cells is the initial pathological abnormality evident in diabetic nephropathy and central to the development of tubulointerstitial injury. Hence, our studies were designed to assess the effects of PPAR{gamma} agonists on the transcription factors activator protein-1 (AP-1) and NF-{kappa}B, the profibrotic cytokine TGF-{beta}1, and the extracellular matrix proteins fibronectin and collagen IV in proximal tubular cells after short-term exposure to high-glucose conditions.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Cell culture. HK-2 cells, a primary human proximal tubular cell line (a gift from Prof. J Charlesworth, Sydney, Australia), were grown in keratinocyte serum-free media (KSFM) supplemented with bovine pituitary extract (20–30 µg/ml) and epidermal growth factor (0.1–0.2 ng/ml, GIBCO). Cell culture media was changed every 48–72 h. These cells were grown at 37°C in a humidified 5% CO2 incubator and were subcultured at 50–80% confluence using 0.05% trypsin-0.02% EDTA (GIBCO).

The clinically available thiazolidinedione pioglitazone (10 µM, Cayman Chemical) and the more selective PPAR{gamma} agonist L-805645 (8 µM, Merck) were used to determine the specific effects of PPAR{gamma} activation in this proximal tubular model. These concentrations were chosen based on their ability to significantly upregulate PPAR{gamma} expression in this model and have been used in previous studies (27).

When 80% confluent, HK-2 cells were exposed to the following experimental conditions for 24 h. For TGF-{beta} ELISA, cells were exposed for 48 h: 1) 5 mM D-glucose (control media); 2) 30 mM D-glucose (ICN Biomedical); 3) 5 mM D-glucose and 25 mM L-glucose (osmotic control, ICN Biomedical); 4) 8 µM L-805645 in 5 mM D-glucose; 5) 8 µM L-805645 in 30 mM D-glucose; 6) 10 µM pioglitazone in 5 mM D-glucose; and 7) 10 µM pioglitazone in 30 mM D-glucose.

As L-805645 and pioglitazone were dissolved in 0.016 and 0.13% DMSO, respectively, additional controls were undertaken to evaluate independent effects of the DMSO at 0.13%.

Nuclear extraction and EMSA for AP-1 and NF-{kappa}B. After exposure to the above-mentioned experimental conditions, nuclear extracts were prepared using a NucBuster Protein Extraction Kit (Novagen, Darmstadt, Germany) as per the manufacturer’s instructions. A digoxygenin (DIG) Gel Shift Kit (Roche Applied Science, Indianapolis, IN) was used in the EMSA. In brief, 25 µg of nuclear extract were incubated with 1 µg poly [d(I-C)] as the nonspecific competitor, 1 µg poly L-lysine in a binding buffer [(in mM) 100 HEPES, pH 7.6, 5 EDTA, 50 (NH4)2SO4, 5 DTT, and 150 KCl, as well as 1% Tween 20, wt/vol] and DIG-labeled AP-1 (5'-CGC TTG ATG AGT CAG CCG GAA-3') or NF-{kappa}B (5'-AGT TGA GGG GAC TTT CCC AGG C-3') consensus oligonucleotide (Promega) for 30 min at room temperature. Unlabeled AP-1 and NF-{kappa}B consensus oligonucleotides were used as specific competitors, respectively. The reaction mixture was electrophoresed through 6% polyacrylamide gels, transferred onto positively charged nylon membrane (Roche Applied Science), and then cross-linked using an UV transilluminator for 3 min. The membrane was subjected to immunological detection using anti-DIG-AP conjugate and chemiluminescence. Results were analyzed using Image J software, and shift bands were measured.

TGF-{beta}1. Cells were seeded at 2 x 105 cells/well in a 24-well plate and grown in KSFM without growth factors for 24 h. At 70% confluence, cells were exposed to the experimental conditions as defined above for 48 h in quadruplicate. Supernatants were then collected, spun, and stored at –20° C until TGF-{beta}1 levels were determined by immunoassay (Promega) as per the manufacturer’s instructions. Cell lysate protein concentration was determined (Bio-Rad), and TGF-{beta}1 levels were corrected for protein content per well.

Western blot analysis. Cells were collected, and the cell pellet was resuspended in cell lysis buffer containing 50 mM Tris·HCl, 150 mM NaCl, 5 mM EDTA (pH 7.4), 0.5% Triton X-100, and protease inhibitors (Roche Diagnostics, Mannheim, Germany). Cell lysate was then sonicated to release total cell proteins, spun at 12,000 rpm at 4°C, and stored at –80°C.

Protein assay (Bio-Rad) was done to determine the protein concentration of the cell lysate. Eighty micrograms of total cell protein were mixed with 6x Laemmli sample buffer containing mercaptoethanol and heated at 95°C for 10 min. Samples were then analyzed by SDS-PAGE in 7.5% gels and electroblotted to Hybond Nitrocellulose membranes (Amersham Pharmacia Biotech, Bucks, UK). Membranes were blocked in Tris-buffered saline containing 0.2% Tween 20 (TTBS) in 5% skim milk for 2–3 h, incubated overnight at 4°C with fibronectin (1:100, NeoMarkers), collagen IV (1:5,000, Abcam, Cambridge, UK), then reprobed with actin (1:300, Santa Cruz) in TTBS containing 5% skim milk. Membranes were washed with TTBS and incubated with horseradish peroxidase-conjugated secondary antibody. Proteins were visualized using the enhanced chemiluminescence detection system (Amersham Pharmacia Biotech). Results were corrected for actin.

Statistical analysis. Results are expressed as a percentage of the mean ± SE of control values. Experiments were performed at least in triplicate or as detailed in the individual experimental protocols. Statistical comparisons between groups were made by ANOVA or unpaired t-tests where appropriate. Analyses were performed using the software package StatView version 5.0 (Abacus Concepts, Berkley, CA). P values <0.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
AP-1. High D-glucose increased the DNA binding of DIG-labeled AP-1 to 140.8 ± 10.9% of control (P < 0.05). Exposure to the osmotic control also increased AP-1 binding to 133.0 ±_14.2% of control (P < 0.05). The high glucose-induced increase in AP-1 was attenuated by concurrent exposure to L-805645 to 82.3 ± 14.4% of control (P < 0.01 vs. high D-glucose). Pioglitazone also abrogated the high glucose-induced increase in AP-1, reducing it to 99.3 ± 12.2% of control values (P < 0.05 vs. high D-glucose) (Fig. 1).



View larger version (31K):
[in this window]
[in a new window]
  		Fig. 1. L-805645 (8 µM) and pioglitazone (10 µM) were able to suppress high D-glucose-induced digoxygenin (DIG)-labeled activator protein-1 (AP-1) binding. HK-2 cells were incubated for 24 h with control media (ctrl), 5 mM D-glucose and 25 mM L-glucose (L-Glu), 30 mM D-glucose (30-D-Glu), 8 µM L-805645 in 30 mM D-glucose, 10 µM pioglitazone (Pio) in 30 mM D-glucose. Nuclear extract preparation and EMSA are as described in METHODS. Top: representative image with shift (top) and free bands (bottom). Bottom: normalized results expressed as means ± SE; n = 3. *P < 0.05 vs. control. **P < 0.05 vs. high D-glucose.

 
TGF-{beta}1. High D-glucose increased total TGF-{beta}1 secretion to 4.82 pg·ml–1·unit protein cell lysate–1 or 139.6 ± 6.5% of control (P < 0.05). This increase was reduced in the presence of L-805645 to 2.93 pg·ml–1·unit protein cell lysate–1 or 68.73 ± 5.7% of control (P < 0.01 vs. high D-glucose). Pioglitazone also reduced high glucose-induced TGF-{beta}1 secretion to 3.77 pg·ml–1·unit protein cell lysate–1 or 112 ± 13.6% (P < 0.05 vs. high D-glucose) (Fig. 2).



View larger version (10K):
[in this window]
[in a new window]
  		Fig. 2. L-805645 (8 µM) and pioglitazone (10 µM) were able to suppress high D-glucose-induced total transforming growth factor-{beta} (TGF-{beta}) secretion. HK-2 cells were incubated for 48 h with control media, 5 mM D glucose and 25 mM L-glucose, 30 mM D-glucose, 8 µM L-805645 in 30 mM D-glucose, 10 µM pioglitazone in 30 mM D-glucose. TGF-{beta} ELISA is as described in METHODS. Results are expressed as absolute values in pg/ml corrected for per unit protein in cell lysate ± SE; n = 4. *P < 0.05 vs. control. **P < 0.01 vs. high D-glucose. {dagger}P < 0.05 vs. D-glucose.

 
Fibronectin. The protein expression of fibronectin, an extracellular matrix protein downstream to TGF-{beta}1, was increased in the presence of high glucose to 156.0 ± 24.9% of control (P < 0.05). The addition of L-805645 and pioglitazone reduced high glucose-induced fibronectin expression to 81.9 ± 16.0 and 57.4 ± 12.7% (both P < 0.01 vs high D-glucose), respectively (Fig. 3).



View larger version (22K):
[in this window]
[in a new window]
  		Fig. 3. L-805645 (8 µM) and pioglitazone (10 µM) were able to suppress high D-glucose-induced fibronectin expression. HK-2 cells were incubated for 24 h with control media, 5 mM D-glucose and 25 mM L-glucose, 30 mM D-glucose, 8 µM L-805645 in 30 mM D-glucose, or 10 µM pioglitazone in 30 mM D-glucose. Western blotting is as described in METHODS. Top: representative image for fibronectin and actin bands. Bottom: normalized results expressed as means ± SE; n = 4. *P < 0.05 vs. control. **P < 0.01 vs. high D-glucose.

 
Collagen IV. There was no significant upregulation of collagen IV expression following short-term exposure to high glucose (110 ± 23.2%; P = not significant), suggesting that the initial increase in extracellular matrix is largely as a result of deposition of noncollagen proteins. Nevertheless, both classes of PPAR{gamma} agonists were able to suppress collagen IV expression to levels below that observed in high-glucose conditions (68.0 ± 14.5%, P < 0.05 and 46.5 ± 11.6%, P < 0.01 vs. high D-glucose following exposure to L-805645 and pioglitazone, respectively) (Fig. 4).



View larger version (26K):
[in this window]
[in a new window]
  		Fig. 4. High D-glucose did not induce collagen IV expression significantly. However, both L-805645 and pioglitazone were able to suppress collagen IV levels. HK-2 cells were incubated for 24 h with control media, 5 mM D-glucose and 25 mM L-glucose, 30 mM D-glucose, 8 µM L-805645 in 5 mM D-glucose, 8 µM L-805645 8 in 30 mM D-glucose, 10 µM pioglitazone in 5 mM D-glucose, or 10 µM pioglitazone in 30 mM D-glucose. Western blotting is as described in METHODS. Top: representative image for collagen IV and actin bands. Bottom: normalized results expressed as means ± SE; n = 3. *P < 0.05 vs. high D-glucose. **P value < 0.01 vs. high D-glucose.

 
NF-{kappa}B. High glucose increased the binding of DIG-labeled NF-{kappa}B to 167.3 ± 22.4% of control (P < 0.05). However, neither of the PPAR{gamma} agonists significantly suppressed glucose-induced NF-{kappa}B binding, as shown in Fig. 5. Interestingly, the presence of even low concentrations of DMSO also increased the binding of DIG-labeled NF-{kappa}B to 159.3 ± 19.3% of control (P < 0.05; not shown in Fig. 5).



View larger version (57K):
[in this window]
[in a new window]
  		Fig. 5. D-glucose increased the binding of DIG-labeled NF-{kappa}B. However, neither of the PPAR{gamma} agonists significantly suppressed glucose-induced NF-{kappa}B binding. Nuclear extract preparation and EMSA are as described in METHODS. Top: representative image with shift (top) and free bands (bottom). Bottom: normalized results expressed as means ± SE; n = 3. *P < 0.05 vs. control.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
TDZs are widely used as insulin-sensitizing agents in the treatment of type 2 diabetes. They appear to exert a renoprotective effect in animal models and in vitro studies, which until recently have focused on mesangial cells (2, 12, 14, 26, 34). Recent work from our laboratory has demonstrated that PPAR{gamma} agonists limit LDL- and albumin-induced proinflammatory responses in the human proximal tubule (37) and reduce extracellular matrix production by human cortical fibroblasts (38). However, their role and function in human proximal tubular cells under high-glucose conditions inherent in diabetic nephropathy have not been well defined. In the present study, we demonstrate that PPAR{gamma} ligands reverse the high glucose-induced profibrotic responses in the proximal tubule. As thickening of the basement membrane of the proximal tubule is the earliest pathological response observed in the development of diabetic nephropathy, these findings suggest that early use of PPAR{gamma} agonists may limit the development of diabetic nephropathy.

The results of these studies suggest that the AP-1 pathway is upregulated following exposure to high-glucose conditions, an effect that is due, at least in part, to the hyperosmolar effect. The TGF-{beta} gene is a known target gene for the transcription factor AP-1 (35). Furthermore, in mesangial cells TZDs prevented high-glucose induction of TGF-{beta}1 promoter activity and elevation of nuclear c-fos (subunit of AP-1) protein levels. TGF-{beta}1 stimulates various extracellular matrix genes, including fibronectin. TZDs also inhibit TGF-{beta}1-induced fibronectin expression in mesangial cells (14). Clearly, our studies demonstrated that TGF-{beta}1 was increased specifically by exposure to high glucose, suggesting downstream specificity of AP-1 activation with respect to target cytokines. Both the TZD and non-TZD PPAR{gamma} agonists reduced AP-1 expression and reversed the high glucose-induced increase in TGF-{beta}1, although the effect was more marked in the presence of the TZD pioglitazone. The increased expression of both AP-1 and TGF-{beta}1 was translated into an increase in fibronectin expression, which was also reversed in the presence of both the TZD and non-TZD agonists. This effect was seen despite the increase in TGF-{beta} seen with DMSO, the vehicle in which L-805645 and pioglitazone were dissolved (data not shown). Hence, these results taken together strongly support the notion that these agonists exert antifibrotic effects in proximal tubular cells by attenuating AP-1, its target, i.e., TGF-{beta}1, and the downstream fibronectin.

We previously showed that short-term exposure to high D-glucose upregulates PPAR{gamma} (27). This could be viewed as a protective compensatory response, which on further upregulation with the use of synthetic agonists, exerts renoprotective effects. This upregulation may be selective or sufficient in limiting the early expression of collagen IV on exposure to high glucose but not fibronectin. Alternatively, collagen IV may be deposited later in the course of fibrosis.

Monocyte chemotactic protein-1 (MCP-1) is known to be increased in diabetic nephropathy and considered to play an important role in the development of progressive tubulointerstitial fibrosis. Specifically, using immunohistochemical and in situ hybridization analyses, MCP-1-positive cells were found to be present in the advanced tubulointerstitial lesions of diabetic nephropathy and correlated with urinary MCP-1 levels (33). Part of the therapeutic benefit of angiotensin-converting enzyme inhibitors is considered to be mediated by a reduction in renal MCP-1 production (1, 16). We have previously demonstrated that a reduction in tubular production of MCP-1 is associated with an upregulation of PPAR{gamma} (27). From our current data, this is independent of NF-{kappa}B regulation. This is in keeping with previous data from our group showing that PPAR{gamma} activation similarly reduces an LDL-induced increase in MCP-1, independently of modification of NF-{kappa}B transcriptional pathway (37). The signaling pathways that govern MCP-1 expression in the human kidney are unknown. Our results suggest that the AP-1 pathway, modified by PPAR{gamma} agonist activity, is likely to be at least in part responsible for reduction of transcription factors known to be involved in profibrotic and also proinflammatory pathways. This is consistent with the known murine MCP-1 promoter, which contains AP-1 and SP-1, in addition to NF-{kappa}B promoter hypermethylation and orphan sites, all of which regulate MCP-1 activity (28). Hence, its modification is of key therapeutic significance. Of note, we found that DMSO vehicle increased NF-{kappa}B binding (data not shown), consistent with recently reported data (19). This is important as it may be a confounding factor limiting the effects of the PPAR{gamma} agonists.

Therapeutic strategies to delay or attenuate the progression of diabetic nephropathy are essential to the treatment of patients with DM. These results provide new knowledge as to whether targeting PPAR{gamma} activation in patients with DM will ultimately reduce the burden of diabetic nephropathy.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
U. Panchapakesan was funded by a Jacquot Research Entry Scholarship. We also acknowledge support by the National Health and Medical Research Council of Australia, Juvenile Diabetes Research Foundation, Diabetes Australia Research Trust, and Merck Laboratories for generously providing us with L-805645.


   FOOTNOTES
 

Address for reprint requests and other correspondence: C. A. Pollock, Dept. of Medicine, Royal North Shore Hospital, NSW 2065, Australia (e-mail: carpol{at}med.usyd.edu.au)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Amann B, Tinzmann R, and Angelkort B. ACE inhibitors improve diabetic nephropathy through suppression of renal MCP-1. Diabetes Care 26: 2421–2425, 2003.[Abstract/Free Full Text]
  2. Asano T, Wakisaka M, Yoshinari M, Iino K, Sonoki K, Iwase M, and Fujishima M. Peroxisome proliferator-activated receptor {gamma}1 (PPAR{gamma}1) expresses in rat mesangial cells and PPAR{gamma} agonists modulate its differentiation. Biochim Biophys Acta 1497: 148–154, 2000.[Medline]
  3. Athyros VG, Mikhailidis DP, Papageorgiou AA, Symeonidis AN, Pehlivanidis AN, Bouloukos VI, and Elisaf M. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J Clin Pathol 57: 728–734, 2004.[Abstract/Free Full Text]
  4. Bakris G, Viberti G, Weston WM, Heise M, Porter LE, and Freed MI. Rosiglitazone reduces urinary albumin excretion in type II diabetes. J Hum Hypertens 17: 7–12, 2003.[CrossRef][ISI][Medline]
  5. Berger J and Wagner JA. Physiological and therapeutic roles of peroxisome proliferator-activated receptors. Diabetes Technol Ther 4: 163–174, 2002.[CrossRef][Medline]
  6. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, and Shahinfar S. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345: 861–869, 2001.[Abstract/Free Full Text]
  7. Buckingham RE, Al-Barazanji KA, Toseland CD, Slaughter M, Connor SC, West A, Bond B, Turner NC, and Clapham JC. Peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats. Diabetes 47: 1326–1334, 1998.[Abstract]
  8. Chen J, Sun Z, Ma J, Gu Y, Yang H, and Lin S. Abstract: non-metabolic protective effects of pioglitazone on diabetic nephropathy induced by streptozotocin in uninephrectomized rat (Abstract). J Am Soc Nephrol 14: 392A, 2003.
  9. Collins R, Armitage J, Parish S, Sleigh P, and Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5,963 people with diabetes: a randomised placebo-controlled trial. Lancet 361: 2005–2016, 2003.[CrossRef][ISI][Medline]
  10. The Diabetes Control and Complications Research Group. Effect of intensive therapy on the development, and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. The Diabetes Control and Complications (DCCT) Research Group. Kidney Int 47: 1703–1720, 1995.[ISI][Medline]
  11. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, and Evans RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR{gamma}. Cell 83: 803–812, 1995.[CrossRef][ISI][Medline]
  12. Ghosh SS, Gehr TW, Ghosh S, Fakhry I, Sica DA, Lyall V, and Schoolwerth AC. PPAR{gamma} ligand attenuates PDGF-induced mesangial cell proliferation: role of MAP kinase. Kidney Int 64: 52–62, 2003.[ISI][Medline]
  13. Guan Y, Zhang Y, and Breyer MD. The role of PPARs in the transcriptional control of cellular processes. Drug News Perspect 15: 147–154, 2002.[CrossRef][ISI][Medline]
  14. Guo B, Koya D, Isono M, Sugimoto T, Kashiwagi A, and Haneda M. Peroxisome proliferator-activated receptor-gamma ligands inhibit TGF-{beta}1-induced fibronectin expression in glomerular mesangial cells. Diabetes 53: 200–208, 2004.[Abstract/Free Full Text]
  15. Imano E, Kanda T, Nakatani Y, Nishida T, Arai K, Motomura M, Kajimoto Y, Yamasaki Y, and Hori M. Effect of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy. Diabetes Care 21: 2135–2139, 1998.[Abstract]
  16. Kato S, Luyckx VA, Ots M, Lee KW, Ziai F, Troy JL, Brenner BM, and MacKenzie HS. Renin-angiotensin blockade lowers MCP-1 expression in diabetic rats. Kidney Int 56: 1037–1048, 1999.[CrossRef][ISI][Medline]
  17. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, and Lehmann JM. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor {gamma} and promotes adipocyte differentiation. Cell 83: 813–819, 1995.[CrossRef][ISI][Medline]
  18. Lebovitz HE, Dole JF, Patwardhan R, Rappaport EB, and Freed MI. Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab 86: 280–288, 2001.[Abstract/Free Full Text]
  19. Lee YR, Shim HJ, Yu HN, Song EK, Park J, Kwon KB, Park JW, Rho HW, Park BH, Han MK, and Kim JS. Dimethylsulfoxide induces upregulation of tumor suppressor protein PTEN through nuclear factor-{kappa}B activation in HL-60 cells. Leuk Res 29: 401–405, 2005.[Medline]
  20. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, and Raz I. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345: 851–860, 2001.[Abstract/Free Full Text]
  21. Ma LJ, Marcantoni C, Linton MF, Fazio S, and Fogo AB. Peroxisome proliferator-activated receptor-{gamma} agonist troglitazone protects against nondiabetic glomerulosclerosis in rats. Kidney Int 59: 1899–1910, 2001.[CrossRef][ISI][Medline]
  22. McCarthy KJ, Routh RE, Shaw W, Walsh K, Welbourne TC, and Johnson JH. Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion. Kidney Int 58: 2341–2350, 2000.[CrossRef][ISI][Medline]
  23. Miyata KS, McCaw SE, Marcus SL, Rachubinski RA, and Capone JP. The peroxisome proliferator-activated receptor interacts with the retinoid X receptor in vivo. Gene 148: 327–330, 1994.[CrossRef][ISI][Medline]
  24. Nagy L, Tontonoz P, Alvarez JG, Chen H, and Evans RM. Oxidized LDL regulates macrophage gene expression through ligand activation of PPAR{gamma}. Cell 93: 229–240, 1998.[CrossRef][ISI][Medline]
  25. National Institute of Diabetes and Digestive and Kidney Diseases. US Renal Data System. Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, 2003.
  26. Nicholas SB, Kawano Y, Wakino S, Collins AR, and Hsueh WA. Expression and function of peroxisome proliferator-activated receptor-{gamma} in mesangial cells. Hypertension 37: 722–727, 2001.[Abstract/Free Full Text]
  27. Panchapakesan U, Pollock CA, and Chen XM. The effect of high glucose and PPAR-{gamma} agonists on PPAR-{gamma} expression and function in HK-2 cells. Am J Physiol Renal Physiol 287: F528–F534, 2004.[Abstract/Free Full Text]
  28. Ping D, Boekhoudt GH, Rogers EM, and Boss JM. Nuclear factor-{kappa}B p65 mediates the assembly and activation of the TNF-responsive element of the murine monocyte chemoattractant-1 gene. J Immunol 162: 727–734, 1999.[Abstract/Free Full Text]
  29. Routh RE, Johnson JH, and McCarthy KJ. Troglitazone suppresses the secretion of type I collagen by mesangial cells in vitro. Kidney Int 61: 1365–1376, 2002.[CrossRef][ISI][Medline]
  30. Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherardi G, Arnoldi F, Ganeva M, Ene-Iordache B, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, and Remuzzi G. Preventing microalbuminuria in type 2 diabetes. N Engl J Med 351: 1941–1951, 2004.[Abstract/Free Full Text]
  31. Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, and Evans RM. PPAR{gamma} promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93: 241–252, 1998.[CrossRef][ISI][Medline]
  32. UK Prospective Diabetes Study Group. Tight blood pressure control, and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 317: 703–713, 1998.[Abstract/Free Full Text]
  33. Wada T, Furuichi K, Sakai N, Iwata Y, Yoshimoto K, Shimizu M, Takeda SI, Takasawa K, Yoshimura M, Kida H, Kobayashi KI, Mukaida N, Naito T, Matsushima K, and Yokoyama H. Up-regulation of monocyte chemoattractant protein-1 in tubulointerstitial lesions of human diabetic nephropathy. Kidney Int 58: 1492–1499, 2000.[CrossRef][ISI][Medline]
  34. Weigert C, Brodbeck K, Bierhaus A, Haring HU, and Schleicher ED. c-Fos-driven transcriptional activation of transforming growth factor {beta}-1: inhibition of high glucose-induced promoter activity by thiazolidinediones. Biochem Biophys Res Commun 304: 301–307, 2003.[CrossRef][ISI][Medline]
  35. Weigert C, Sauer U, Brodbeck K, Pfeiffer A, Haring HU, and Schleicher ED. AP-1 proteins mediate hyperglycemia-induced activation of the human TGF-{beta}1 promoter in mesangial cells. J Am Soc Nephrol 11: 2007–2016, 2000.[Abstract/Free Full Text]
  36. Xu L, Glass CK, and Rosenfeld MG. Coactivator and corepressor complexes in nuclear receptor function. Curr Opin Genet Dev 9: 140–147, 1999.[CrossRef][ISI][Medline]
  37. Zafiriou S, Stanners SR, Polhill TS, Poronnik P, and Pollock CA. Pioglitazone increases renal tubular cell albumin uptake but limits proinflammatory and fibrotic responses. Kidney Int 65: 1647–1653, 2004.[CrossRef][ISI][Medline]
  38. Zafiriou S, Stanners SR, Saad S, Polhill TS, Poronnik P, and Pollock CA. Pioglitazone inhibits cell growth and reduces matrix production in human kidney fibroblasts. J Am Soc Nephrol 16: 638–645, 2005.[Abstract/Free Full Text]
  39. Zhang Y, Park CW, Zheng F, Fan X, Striker GE, Breyer MD, and Guan Y. Endogenous PPAR{gamma} activity ameliorates diabetic nephropathy (Abstract). J Am Soc Nephrol 14: 392A, 2003.



This article has been cited by other articles:


Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J. E. Milam, V. G. Keshamouni, S. H. Phan, B. Hu, S. R. Gangireddy, C. M. Hogaboam, T. J. Standiford, V. J. Thannickal, and R. C. Reddy
PPAR-{gamma} agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis
Am J Physiol Lung Cell Mol Physiol, May 1, 2008; 294(5): L891 - L901.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
X. Ruan, F. Zheng, and Y. Guan
PPARs and the kidney in metabolic syndrome
Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1032 - F1047.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
P. Boor, K. Sebekova, T. Ostendorf, and J. Floege
Treatment targets in renal fibrosis
Nephrol. Dial. Transplant., December 1, 2007; 22(12): 3391 - 3407.
[Full Text] [PDF]

Home page
 DiabetesHome page
D. R. Cha, X. Zhang, Y. Zhang, J. Wu, D. Su, J. Y. Han, X. Fang, B. Yu, M. D. Breyer, and Y. Guan
Peroxisome Proliferator Activated Receptor {alpha}/{gamma} Dual Agonist Tesaglitazar Attenuates Diabetic Nephropathy in db/db Mice
Diabetes, August 1, 2007; 56(8): 2036 - 2045.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
X. Li, H. Kimura, K. Hirota, H. Sugimoto, N. Kimura, N. Takahashi, H. Fujii, and H. Yoshida
Hypoxia reduces the expression and anti-inflammatory effects of peroxisome proliferator-activated receptor-{gamma} in human proximal renal tubular cells
Nephrol. Dial. Transplant., April 1, 2007; 22(4): 1041 - 1051.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
W. Qi, X. Chen, J. Holian, E. Mreich, S. Twigg, R. E. Gilbert, and C. A. Pollock
Transforming growth factor-beta1 differentially mediates fibronectin and inflammatory cytokine expression in kidney tubular cells
Am J Physiol Renal Physiol, November 1, 2006; 291(5): F1070 - F1077.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
S. C.W. Tang, J. C.K. Leung, L. Y.Y. Chan, A. W.L. Tsang, and K. N. Lai
Activation of Tubular Epithelial Cells in Diabetic Nephropathy and the Role of the Peroxisome Proliferator-Activated Receptor-{gamma} Agonist
J. Am. Soc. Nephrol., June 1, 2006; 17(6): 1633 - 1643.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
289/5/F1153    most recent
00097.2005v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (17)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Panchapakesan, U.
Right arrow Articles by Chen, X.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Panchapakesan, U.
Right arrow Articles by Chen, X.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2005 by the American Physiological Society.