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

Abstract

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.

Peroxisome proliferator-activated receptor gamma agonists in renal disease

“…Pioglitazone also improved the urinary albumin/creatinine ratio (ACR) and the glomerular and Bowman's capsule volume ratios, and reduced endothelial constitutive nitric oxide synthetase (ecNOS) in the endothelium of glomerular vessels in early stage of type 2 diabetic nephropathy in mice (75). An increase in renal tubular cell albumin uptake induced by pioglitazone has also been reported (76). The urinary albumin excretion rate (AER) was significantly decreased after 12 weeks of treatment with thiazolidinediones, and there was a suppression of the loss of anionic sites of glomerular basement membranes (GBM) in streptozotocin-induced diabetic spontaneous hypertensive rats (73).…”

Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone

“…Accordingly, PPARγ agonists are now well-established drugs widely used in the treatment of type 2 diabetes [37,39]. PPARγ agonists have further been shown to decrease proteinuria [5] and counteract renal fibrosis [30,50].…”

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).…”