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

Abstract

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.

Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats

“…Mezzano et al [30] reported that the activation of NF-κB and chemokines such as CCL2 and RANTES (regulated upon activation, normal T expressed and secreted) was strongly upregulated in renal tissues of human diabetic nephropathy. Moreover, high glucose upregulates peroxisome proliferator-activated receptor-γ (PPAR-γ), and PPAR-γ agonists exert antifibrotic, anti-proliferative and anti-inflammatory effects in renal proximal tubular cells under high glucose conditions by attenuating the increase in activator protein-1, TGFB1 and the downstream production of the extracellular matrix protein [31,32]. These data also suggest that inflammatory mechanisms are involved in the progression of diabetic nephropathy.…”

Peroxisome Proliferator-activated Receptor γ Interacts with CIITA·RFX5 Complex to Repress Type I Collagen Gene Expression

“…The thiazolidinedione compounds and certain prostaglan- dins have been used to demonstrate that activation of PPAR␥ inhibits collagen synthesis (18) and fibrosis in lung (14,15,19,57), kidney (8,9,58), liver (10,11,33,36,59), cardiac fibroblasts (60), and skin (61). The issue of endogenous ligand for PPAR␥ in cells has been controversial.…”

“…Synthetic antagonists of PPAR␥ are also available to inhibit PPAR␥ activity (5-7). Activation of PPAR␥ by agonists attenuates fibrosis in several organs, including kidneys (8,9), liver (10,11), heart (13), and lungs (14,15), and arteries in atherosclerosis (12) . Several studies suggest that PPAR␥ inhibits extracellular matrix synthesis, including collagen (16 -18).…”

Phase I Trial of Rosiglitazone in FSGS

“…Administration of rosiglitazone (5 mg/kg for 20 d) to pregnant diabetic rats leads to inhibition of mesangial cell proliferation, downregulation of apoptosis, and reduced responsiveness to angiotensin II (1). Pioglitazone, another peroxisome proliferator-activated receptor-␥ agonist, exerts antifibrotic effects at 10 M in renal tubular cells exposed to high glucose (2) and reduces extracellular matrix production at 1 to 3 M after incubation with LDL (3). In puromycin aminonucleoside nephropathy, there is a decrease in podocyte injury, glomerulosclerosis, infiltrating glomerular macrophages, and plasminogen activator inhibitor-1 mRNA expression after treatment with pioglitazone, 10 mg/kg/d for 6 to 12 wk (4).…”