Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion

McCarthy, Kevin; Routh, Robert; Shaw, Wayne; Walsh, Kathleen M.; Welbourne, T. C.; Johnson, John H.

doi:10.1046/j.1523-1755.2000.00418.x

Cited by 94 publications

(77 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Insulin resistance is one of the important pathogenic factors for the diabetic nephropathy in type 2 diabetes. Indeed, improvement of insulin resistance by thiazolidinediones resulted in the reduction of albuminuria in diabetic nephropathy (33). Therefore, we examined the effects of pioglitazone on the gene expression profiles in db/db mice.…”

Section: Resultsmentioning

confidence: 99%

Altered Gene Expression Related to Glomerulogenesis and Podocyte Structure in Early Diabetic Nephropathy of db/db Mice and Its Restoration by Pioglitazone

et al. 2006

View full text Add to dashboard Cite

Glomerular injury plays a pivotal role in the development of diabetic nephropathy. To elucidate molecular mechanisms underlying diabetic glomerulopathy, we compared glomerular gene expression profiles of db/db mice with those of db/m control mice at a normoalbuminuric stage characterized by hyperglycemia and at an early stage of diabetic nephropathy with elevated albuminuria, using cDNA microarray. In db/db mice at the normoalbuminuric stage, hypoxia-inducible factor-1␣ (HIF-1␣), ephrin B2, glomerular epithelial protein 1, and Pod-1, which play key roles in glomerulogenesis, were already upregulated in parallel with an alteration of genes related to glucose metabolism, lipid metabolism, and oxidative stress. Podocyte structure-related genes, actinin 4␣ and dystroglycan 1 (DG1), were also significantly upregulated at an early stage. The alteration in the expression of these genes was confirmed by quantitative RT-PCR. Through pioglitazone treatment, gene expression of ephrin B2, Pod-1, actinin 4␣, and DG1, as well as that of oxidative stress and lipid metabolism, was restored concomitant with attenuation of albuminuria. In addition, HIF-1␣ protein expression was partially attenuated by pioglitazone. These results suggest that not only metabolic alteration and oxidative stress, but also the alteration of gene expression related to glomerulogenesis and podocyte structure, may be involved in the pathogenesis of early diabetic glomerulopathy in type 2 diabetes. Diabetes

show abstract

Section: Resultsmentioning

confidence: 99%

Altered Gene Expression Related to Glomerulogenesis and Podocyte Structure in Early Diabetic Nephropathy of db/db Mice and Its Restoration by Pioglitazone

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Rosiglitazone was shown to decrease atherosclerosis development in male LDL-receptor-deficient mice [3] and in diabetic and non-diabetic male apolipoprotein-E-deficient mice [4]. Troglitazone and rosiglitazone were shown to decrease the development of glomerulosclerosis in rats [9,10,11]. In one of these studies, the kidneys were stained for the glomerular mesangial basement membrane chondroitin sulphate proteoglycans, and the data suggested that the inhibitory effect of troglitazone on diabetic glomerulosclerosis may be related to reduced proteoglycan synthesis [10].…”

Section: Introductionmentioning

confidence: 97%

Thiazolidinediones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans

et al. 2004

View full text Add to dashboard Cite

Aims/hypothesis. Retention of atherogenic lipoproteins in the artery wall by proteoglycans is a key step in the development of atherosclerosis. Thiazolidinediones have been shown to reduce atherosclerosis in mouse models. The aim of this study was to determine whether thiazolidinediones modify vascular proteoglycan synthesis in a way that decreases LDL binding. Methods. Primate aortic smooth muscle cells were exposed to troglitazone or rosiglitazone, or no stimulus at all for a 24-hour steady-state labelling period. Sulphate incorporation, size and LDL binding affinity of proteoglycans were determined. Proteoglycans secreted by cells in the presence or absence of troglitazone were separated into large and small classes by size exclusion chromatography, and LDL binding affinity was determined. Results. Proteoglycans synthesised by cells exposed to troglitazone or rosiglitazone were smaller, with decreased sulphate incorporation and decreased LDL binding affinity. However, troglitazone had a greater effect than rosiglitazone. Troglitazone reduced the LDL binding affinities of both the large and small proteoglycans compared with control. The binding differences persisted when glycosaminoglycan chains released from proteoglycans were incubated with LDL, indicating that troglitazone affects the glycosaminoglycan synthetic machinery of these cells. Conclusions/interpretation. Thiazolidinediones decrease the LDL binding affinity of the proteoglycans synthesised by primate aortic smooth muscle cells. This could, in part, account for the reduced atherosclerosis observed in animal models.

show abstract

“…Furthermore, naturally occurring or synthetic ligands of PPAR␥ have been shown to inhibit proliferation (25), myofibroblast transdifferentiation (26), and collagen synthesis (27,28) in hepatic and pancreatic stellate cells. Long-term troglitazone administration prevented the development of glomerulosclerosis (29) and pancreatic fibrosis (30) in rodent models of diabetes. Together, these findings indicate that activation of PPAR␥ by naturally occurring ligands or synthetic agonists causes repression of profibrotic responses in vitro and is associated with reduction or prevention of organ fibrosis.…”

mentioning

confidence: 96%

Disruption of transforming growth factor β signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator–activated receptor γ

Ghosh¹,

Bhattacharyya²,

Lakos³

et al. 2004

Arthritis & Rheumatism

188

168

View full text Add to dashboard Cite

Objective. In fibroblasts, transforming growth factor ␤ (TGF␤) stimulates collagen synthesis and myofibroblast transdifferentiation through the Smad intracellular signal transduction pathway. TGF␤-mediated fibroblast activation is the hallmark of scleroderma and related fibrotic conditions, and disrupting the intracellular TGF␤/Smad signaling may provide a novel approach to controlling fibrosis. Because of its potential role in modulating inflammatory and fibrotic responses, we examined the expression of the nuclear hormone receptor peroxisome proliferator-activated receptor ␥ (PPAR␥) in normal skin fibroblasts and its effect on TGF␤-induced cellular responses.Methods. The expression and activity of PPAR␥ in normal dermal fibroblasts were examined by Northern and Western blot analyses, immunocytochemistry, flow cytometry, and transient transfections with reporter constructs. The same approaches were used to evaluate the effects of PPAR␥ activation by naturally occurring and synthetic ligands on collagen synthesis and ␣-smooth muscle actin (␣-SMA) expression. Modulation of Smad-mediated transcriptional responses was examined by transient transfection assays using wild-type and dominant-negative PPAR␥ expression constructs. Abnormal synthesis and tissue accumulation of collagen are hallmarks of scleroderma and are responsible for the damage and failure of affected organs. Lesional scleroderma fibroblasts display an activated phenotype characterized by accelerated transcription of genes coding for collagen and other extracellular matrix proteins, increased expression of cell surface receptors for transforming growth factor ␤ (TGF␤), and sustained production of TGF␤, connective tissue growth factor, Supported by grants from the NIH (AR-46390 and AR-42309) and the Scleroderma Foundation. Results

show abstract

Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion

Abstract: Therapeutic intervention with the thiazolidinedione troglitazone halts the early onset and progression of mesangial expansion in the ZDF/Gmitrade mark rat, preventing the development of glomerulosclerosis in this animal model of type 2 diabetes mellitus.

Cited by 94 publications

References 47 publications

Altered Gene Expression Related to Glomerulogenesis and Podocyte Structure in Early Diabetic Nephropathy of db/db Mice and Its Restoration by Pioglitazone

Altered Gene Expression Related to Glomerulogenesis and Podocyte Structure in Early Diabetic Nephropathy of db/db Mice and Its Restoration by Pioglitazone

Thiazolidinediones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans

Disruption of transforming growth factor β signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator–activated receptor γ

Contact Info

Product

Resources

About