Troglitazone suppresses the secretion of type I collagen by mesangial cells in vitro

Routh, Robert; Johnson, John H.; McCarthy, Kevin

doi:10.1046/j.1523-1755.2002.00277.x

Cited by 60 publications

(41 citation statements)

References 47 publications

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“…Thus, the anti-inflammatory effects of rosiglitazone may contribute to the marked renal protection in the current study. Finally, PPARg is constitutively expressed in glomeruli, particularly in mesangial cells (Nicholas et al 2001), and PPARg agonists reduce mesangial cell collagen production (Routh et al 2002). Likewise, in this study, rosiglitazone reduced intraglomerular collagen IV expression and glomerular and tubulointerstitial fibrosis.…”

Section: Discussionsupporting

confidence: 68%

Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF1 rats

Bilan¹,

Salah²,

Bastacky³

et al. 2011

Journal of Endocrinology

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Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Yet the pathogenic mechanisms underlying the development of DN are not fully defined, partially due to lack of suitable models that mimic the complex pathogenesis of renal disease in diabetic patients. In this study, we describe early and late renal manifestations of DN and renal responses to long-term treatments with rosiglitazone or high-dose enalapril in ZSF1 rats, a model of metabolic syndrome, diabetes, and chronic renal disease. At 8 weeks of age, obese ZSF1 rats developed metabolic syndrome and diabetes (hyperglycemia, glucosuria, hyperlipidemia, and hypertension) and early signs of renal disease (proteinuria, glomerular collagen IV deposition, tubulointerstitial inflammation, and renal hypertrophy). By 32 weeks of age, animals developed renal histopathology consistent with DN, including mesangial expansion, glomerulosclerosis, tubulointerstitial inflammation and fibrosis, tubular dilation and atrophy, and arteriolar thickening. Rosiglitazone markedly increased body weight but reduced food intake, improved glucose control, and attenuated hyperlipidemia and liver and kidney injury. In contrast, rosiglitazone markedly increased cardiac hypertrophy via a blood pressure-independent mechanism. High-dose enalapril did not improve glucose homeostasis, but normalized blood pressure, and nearly prevented diabetic renal injury. The ZSF1 model thus detects the clinical observations seen with rosiglitazone and enalapril in terms of primary and secondary endpoints of cardiac and renal effects. This and previous reports indicate that the obese ZSF1 rat meets currently accepted criteria for progressive experimental diabetic renal disease in rodents, suggesting that this may be the best available rat model for simulation of human DN.

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Section: Discussionsupporting

confidence: 68%

Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF1 rats

Bilan¹,

Salah²,

Bastacky³

et al. 2011

Journal of Endocrinology

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“…Of the 379 genes robustly regulated by two structurally distinct PPAR␥ agonists in EWAT of db/db mice, 33 encoded for known secreted proteins. Not surprisingly, a few genes known to be regulated by PPAR␥, such as adiponectin (Combs et al, 2002), lipoprotein lipase (Auwerx et al, 1996), laminin ␤3 (Routh et al, 2002), FGF21 (Wang et al, 2008), and TNF␣ (Singh Ahuja et al, 2001) were identified. The other genes in Table 1 were not previously associated with PPAR␥ but are known to be implicated in various pathways such as inflammation, lipid metabolism, and cell growth.…”

Section: Discussionmentioning

confidence: 99%

“…1B). A subset of the 33 genes has previously been shown to be regulated at the transcript level by PPAR␥ agonists [e.g., adiponectin (Adipoq; Combs et al, 2002), FGF21 (Fgf21; Wang et al, 2008), lipoprotein lipase (Lpl; Auwerx et al, 1996), Laminin b3 (Lamb3; Routh et al, 2002), and TNF␣ (Tnf; Singh Ahuja et al, 2001)] (Table 1). Adiponectin, FGF21, and lipoprotein lipase were up-regulated by PPAR␥ agonist treatment, whereas Laminin b3 and TNF␣ were down-regulated (Table 1).…”

Section: Identification Of Genes Encoding For Secreted Proteins Regulmentioning

confidence: 99%

Adipose Fibroblast Growth Factor 21 Is Up-Regulated by Peroxisome Proliferator-Activated Receptor γ and Altered Metabolic States

Muise¹,

Azzolina²,

Kuo³

et al. 2008

Mol Pharmacol

265

223

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Adipose tissue is a metabolically responsive endocrine organ that secretes a myriad of adipokines. Antidiabetic drugs such as peroxisome proliferator-activated receptor (PPAR) ␥ agonists target adipose tissue gene expression and correct hyperglycemia via whole-body insulin sensitization. The mechanism by which altered gene expression in adipose tissue affects liver and muscle insulin sensitivity (and thus glucose homeostasis) is not fully understood. One possible mechanism involves the alteration in adipokine secretion, in particular the up-regulation of secreted factors that increase whole-body insulin sensitivity. Here, we report the use of transcriptional profiling to identify genes encoding for secreted proteins the expression of which is regulated by PPAR␥ agonists. Of the 379 genes robustly regulated by two structurally distinct PPAR␥ agonists in the epididymal white adipose tissue (EWAT) of db/db mice, 33 encoded for known secreted proteins, one of which was FGF21. Although FGF21 was recently reported to be up-regulated in cultured adipocytes by PPAR␥ agonists and in liver by PPAR␣ agonists and induction of ketotic states, we demonstrate that the protein is transcriptionally up-regulated in adipose tissue in vivo by PPAR␥ agonist treatment and under a variety of physiological conditions, including fasting and high fat diet feeding. In addition, we found that circulating levels of FGF21 protein were increased upon treatment with PPAR␥ agonists and under ketogenic states. These results suggest a role for FGF21 in mediating the antidiabetic activities of PPAR␥ agonists.

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“…In addition to the improved metabolic control, it is possible that PPAR␥ agonists have more direct beneficial actions on the kidney because constitutively expressed PPAR␥ are found in glomeruli, particularly mesangial cells (Asano et al, 2000;Nicholas et al, 2001) and PPAR␥ agonists reduce type I collagen synthesis in cultured glomerular mesangial cells (Routh et al, 2002;Zheng et al, 2002). In addition to directly inhibiting glomerular collagen synthesis, PPAR␥ agonist may also act indirectly, via its anti-inflammatory action.…”

Section: Ppar␥ Agonists Protect the Kidney Better Than Acei 857mentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ Agonist Provides Superior Renal Protection versus Angiotensin-Converting Enzyme Inhibition in a Rat Model of Type 2 Diabetes with Obesity

Baylis¹,

Atzpodien²,

Freshour³

et al. 2003

J Pharmacol Exp Ther

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The inbred obese Zucker (ZDF/Gmi, fa/fa) rat develops severe hyperglycemia and also exhibits severe renal disease. In this study, we compared the relative benefits of long-term treatment with angiotensin-converting enzyme inhibition (ACEI) to a peroxisome proliferator-activated receptor ␥ (PPAR␥) agonist. Four groups of obese inbred Zucker rats were studied over a 6-month observation period; untreated animals, rats treated with ACEI alone, rats treated with PPAR␥ agonist alone, and rats treated with a combination of ACEI and PPAR␥ agonist. PPAR␥ agonist treatment normalized plasma glucose and led to massive increases in body weight. Both ACEI and PPAR␥ agonist were effective in reducing the proteinuria and glomerular and tubular kidney damage. However, the PPAR␥ agonist exerted superior renal protection compared with ACEI, in this model of spontaneously occurring chronic renal disease in the diabetic, obese inbred Zucker rat. Of note, although ACEI lowered blood pressure, there was no difference in glomerular blood pressure in any group at the end of the study. The glomerular filtration rate (GFR) was improved by ACEI with a borderline effect of PPAR␥ agonist alone. A mild additive protection on GFR and tubulointerstitial damage was seen with the combination. Based on the literature it is likely that the superior protection by PPAR␥ agonist versus glomerular and tubular damage as well as proteinuria extends beyond glycemic and lipidmic control and also reflects direct, protective intrarenal actions of the PPAR␥ agonists.

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Troglitazone suppresses the secretion of type I collagen by mesangial cells in vitro

Cited by 60 publications

References 47 publications

Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF1 rats

Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF1 rats

Adipose Fibroblast Growth Factor 21 Is Up-Regulated by Peroxisome Proliferator-Activated Receptor γ and Altered Metabolic States

Peroxisome Proliferator-Activated Receptor γ Agonist Provides Superior Renal Protection versus Angiotensin-Converting Enzyme Inhibition in a Rat Model of Type 2 Diabetes with Obesity

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