Peroxisome proliferator-activated receptor γ1 (PPARγ1) expresses in rat mesangial cells and PPARγ agonists modulate its differentiation

Asano, Tomonari; Wakisaka, Masanori; Yoshinari, Mototaka; Iino, Kenzo; Sonoki, Kazuo; Iwase, Masanori; Fujishima, Masatoshi

doi:10.1016/s0167-4889(00)00054-9

Cited by 78 publications

(58 citation statements)

References 24 publications

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“…However, subsequently, PPAR-␥ has been confirmed in human kidney (20,21), and several groups have since identified the presence of PPAR-␥ message and protein in major components of the glomerulus, in mesangial cells, and in endothelial cells in animal models (9,22,23). Studies in our laboratory have also confirmed that in several in vitro proximal tubular cell models, these cells also express PPAR-␥ (7,15).…”

Section: Discussionmentioning

confidence: 61%

Pioglitazone Inhibits Cell Growth and Reduces Matrix Production in Human Kidney Fibroblasts

Zafiriou¹,

Stanners²,

Saad³

et al. 2005

Journal of the American Society of Nephrology

106

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Peroxisome proliferator-activated receptor-␥ (PPAR-␥) agonists are increasingly used in patients with diabetes, and small studies have suggested a beneficial effect on renal function, but their effects on extracellular matrix (ECM) turnover are unknown. The aims of this study were to investigate the effects of the PPAR-␥ agonist pioglitazone on growth and matrix production in human cortical fibroblasts (CF). Cell growth and ECM production and turnover were measured in human CF in the presence and absence of 1 and 3 M pioglitazone. Exposure of CF to pioglitazone caused an antiproliferative (P < 0.0001) and hypertrophic (P < 0.0001) effect; reduced type IV collagen secretion (P < 0.01), fibronectin secretion (P < 0.0001), and proline incorporation (P < 0.0001); decreased MMP-9 activity (P < 0.05); and reduced tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 secretion (P < 0.001 and P < 0.0001, respectively). These effects were independent of TGF-␤1. A reduction in ECM production was similarly observed when CF were exposed to a selective PPAR-␥ agonist (L-805645) in concentrations that caused no toxicity, confirming the antifibrotic effects of pioglitazone were mediated through a PPAR-␥-dependent mechanism. Exposure of CF to high glucose conditions induced an increase in the expression of collagen IV (P < 0.05), which was reversed both in the presence of pioglitazone (1 and 3 M) and by L-805645. In summary, exposure of human CF to pioglitazone causes an antiproliferative effect and reduces ECM production through mechanisms that include reducing TIMP activity, independent of TGF-␤1. These studies suggest that the PPAR-␥ agonists may have a specific role in ameliorating the course of progressive tubulointerstitial fibrosis under both normoglycemic and hyperglycemic states.

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Section: Discussionmentioning

confidence: 61%

Pioglitazone Inhibits Cell Growth and Reduces Matrix Production in Human Kidney Fibroblasts

Zafiriou¹,

Stanners²,

Saad³

et al. 2005

Journal of the American Society of Nephrology

106

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“…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␥ agonists limit LDL-and albumin-induced proinflammatory responses in the human proximal tubule (37) and reduce extracellular matrix production by human cortical fibroblasts (38).…”

Section: Discussionmentioning

confidence: 99%

“…The renoprotective benefit of PPAR␥ agonists is further suggested by studies in nondiabetic models of renal injury, such as the 5/6-nephrectomy model, where activation of PPAR␥ reduced glomerulosclerosis (21). In vitro studies have focused on the use of mesangial cells where PPAR␥ has been well characterized (2,26), with specific PPAR␥ 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)-␤ 1 -dependent mechanism (34). In mesangial cells, pioglitazone has been shown to inhibit TGF-␤-induced fibronectin production (14).…”

mentioning

confidence: 99%

PPARγ agonists exert antifibrotic effects in renal tubular cells exposed to high glucose

Panchapakesan¹,

Sumual²,

Pollock³

et al. 2005

American Journal of Physiology-Renal Physiology

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Collagen IV was not induced by high D-glucose. L-805645 and pioglitazone suppressed collagen IV to 68.0 Ϯ 14.5 (P Ͻ 0.05) and 46.5 Ϯ 11.6% (P Ͻ 0.01) vs. high D-glucose, respectively. High D-glucose increased the nuclear binding of NF-B to 167 Ϯ 22.4% (P Ͻ 0.05), which was not modified with PPAR␥ agonists. In conclusion, PPAR␥ agonists exert antifibrotic effects in human PTC in high glucose by attenuating the increase in AP-1, TGF-␤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␥ agonists may show promise.PPAR␥ 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␥ like the thiazolidinediones (TZDs) are widely used as insulin-sensitizing agents in patients with type 2 DM.

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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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Peroxisome proliferator-activated receptor γ1 (PPARγ1) expresses in rat mesangial cells and PPARγ agonists modulate its differentiation

Cited by 78 publications

References 24 publications

Pioglitazone Inhibits Cell Growth and Reduces Matrix Production in Human Kidney Fibroblasts

Pioglitazone Inhibits Cell Growth and Reduces Matrix Production in Human Kidney Fibroblasts

PPARγ agonists exert antifibrotic effects in renal tubular cells exposed to high glucose

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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