Effect of Troglitazene on Microalbuminuria in Patients With Incipient Diabetic Nephropathy

Imano, Eiichi; Kanda, Tsutomu; Nakatani, Yoichiro; Nishida, Tsutomu; Arai, Katsumi; Motomura, Masaaki; Kajimoto, Yoshitaka; Yamasaki, Yoshimitsu; Hori, Masatsugu

doi:10.2337/diacare.21.12.2135

Cited by 184 publications

(110 citation statements)

References 13 publications

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“…In the context of renal disease, PPARγ agonists have been shown to reduce microalbuminuria in patients with diabetic nephropathy [7][8][9][10], although the mechanisms for this are not fully understood. Regulation of renal filtration occurs at the level of the glomerular filtration barrier, which is comprised of endothelial cells, podocytes and an intervening glomerular basement membrane.…”

Section: Introductionmentioning

confidence: 99%

Rosiglitazone enhances glucose uptake in glomerular podocytes using the glucose transporter GLUT1

et al. 2009

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Aims/hypothesis Peroxisome proliferator-activated receptor (PPAR) γ agonists are used increasingly in the treatment of type 2 diabetes. In the context of renal disease, PPARγ agonists reduce microalbuminuria in diabetic nephropathy; however, the mechanisms underlying this effect are unknown. Glomerular podocytes are newly characterised insulin-sensitive cells and there is good evidence that they are targeted in diabetic nephropathy. In this study we investigated the functional and molecular effects of the PPARγ agonist rosiglitazone on human podocytes. Methods Conditionally immortalised human podocytes were cultured with rosiglitazone and functional effects were measured with glucose-uptake assays. The effect of rosiglitazone on glucose uptake was also measured in 3T3-L1 adipocytes, nephrin-deficient podocytes, human glomerular endothelial cells, proximal tubular cells and podocytes treated with the NEFA palmitate. The role of the glucose transporter GLUT1 was investigated with immunofluorescence and small interfering RNA knockdown and the plasma membrane expression of GLUT1 was determined with bis-mannose photolabelling. Results Rosiglitazone significantly increased glucose uptake in wild-type podocytes and this was associated with translocation of GLUT1 to the plasma membrane. This effect was blocked with GLUT1 small interfering RNA. Nephrin-deficient podocytes, glomerular endothelial cells and proximal tubular cells did not increase glucose uptake in response to either insulin or rosiglitazone. Furthermore, rosiglitazone significantly increased basal and insulinstimulated glucose uptake when podocytes were treated with the NEFA palmitate. Conclusions/interpretation In conclusion, rosiglitazone has a direct and protective effect on glucose uptake in wild-type human podocytes. This represents a novel mechanism by which PPARγ agonists may improve podocyte function in diabetic nephropathy.

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Section: Introductionmentioning

confidence: 99%

Rosiglitazone enhances glucose uptake in glomerular podocytes using the glucose transporter GLUT1

et al. 2009

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“…PPAR-␥2, expressed in vascular smooth muscle cells, mesangial cells, and macrophages, is a ligand-activated transcription factor and a member of the steroid receptor superfamily (11), which has been shown to be involved in lipid and glucose metabolism, fatty acid transport, and cell differentiation (12). Most interesting is that recently developed compounds such as the thiazolidinediones (TZDs) act as PPAR-␥ ligands (13,14) and have been reported to decrease albuminuria in patients with early diabetic nephropathy (15), possibly pointing to a role of PPAR-␥ in the development of this disease-associated microvascular phenotype. We therefore investigated whether Pro12Ala, a recently identified functional genetic polymorphism in the PPAR-␥2 gene and previously reported to be associated with type 2 diabetes (16), was also related to type 2 diabetes-associated disease phenotypes in patients of European ancestry.…”

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confidence: 99%

Peroxisome Proliferator-Activated Receptor-γ2 Polymorphism Pro12Ala Is Associated With Nephropathy in Type 2 Diabetes

et al. 2002

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The Pro12Ala polymorphism of the gene encoding the peroxisome proliferator-activated receptor (PPAR)-␥2 has recently been shown to be associated with type 2 diabetes. In the present analysis, we investigated whether PPAR-␥2 Pro12Ala was associated with microvascular complications of type 2 diabetes, such as albuminuria, end-stage renal failure (ESRF), or retinopathy. A total of 445 patients with type 2 diabetes who were enrolled in the Berlin Diabetes Mellitus Study and in whom we determined albuminuria and the presence of ESRF and retinopathy were genotyped for the PPAR-␥2 Pro12Ala polymorphism. We also measured potentially important covariables, such as blood pressure, BMI, duration of diabetes, glycosylated hemoglobin, serum creatinine, and serum lipids. Among 445 patients with type 2 diabetes (mean age 59.3 years), the Pro12Ala genotype distribution was in Hardy-Weinberg equilibrium (P ‫؍‬ 0.42). The Ala12 allele frequency was 0.14. With adjustment for covariables, the 118 Ala12 allele carriers had significantly lower urinary albumin excretion (UAE) than the 327 noncarriers (17.1 vs. 25.8 mg/d; P ‫؍‬ 0.01). The percentage decrease in UAE observed in PPAR-␥ Ala12 allele carriers relative to noncarriers (P ‫؍‬ 0.003) rose from 0.2% (P ‫؍‬ 0.99) to 54% (P ‫؍‬ 0.008) and to 70% (P ‫؍‬ 0.01) when the duration of diabetes increased from <10 years to 10 -19 years and to >20 years, respectively. Similarly, the odds ratios of having albuminuria decreased from 1.22 (P ‫؍‬ 0.54) to 0.61 (P ‫؍‬ 0.23) and to 0.11 (P ‫؍‬ 0.007), respectively. Among patients with type 2 diabetes, PPAR-␥2 Ala12 allele carriers had significantly lower UAE and tended to develop overt proteinuria less frequently. These observations suggest a protective effect of the Ala12 allele in relation to diabetic nephropathy. Diabetes 51: 2653-2657, 2002

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“…146 Beyond their hypoglycemic actions, PPARЎ agonists exert a number of beneficial effects in diabetes including improvement in endothelial function, 147,148 reduction in pro-atherogenic inflammatory markers 149 and angiotensin-I and -II, 150 down regulation of AT 1 mRNA and protein in vascular smooth muscle cells, 151,152 decrease in urine endothelin-1 secretion, 153 attenuated lipid accumulation and its related injury in mesangial cells, 154,155 and inhibition of glomerular and tubular cell proliferation 156,157 . Several animal [158][159][160][161][162][163] and human studies 153,[164][165][166][167][168][169][170][171][172][173][174][175] using various TZDs have demonstrated a reduction in proteinuria and BP. Unfortunately; most of these studies were of short duration averaging 1-9 months in the animal studies 158-163 and 3-12 months in human studies.…”

Section: Emerging Therapeutic Agents For Diabetic Nephropathy Thiazolmentioning

confidence: 99%

“…Unfortunately; most of these studies were of short duration averaging 1-9 months in the animal studies 158-163 and 3-12 months in human studies. 153,[164][165][166][167][168][169][170][171][172][173][174][175] The use of TZDs has become less frequent due to higher rates of cardiovascular complications. A recent observational, retrospective, inception cohort of 227,571 Medicare patients who were treated with rosiglitazone or pioglitazone for a 12-month period and followed for up to 3 years after initiation of therapy showed rosiglitazone was associated with a higher risk of cardiovascular complications and all-cause mortality in patients 65 years or older compared with pioglitazone.…”

Section: Emerging Therapeutic Agents For Diabetic Nephropathy Thiazolmentioning

confidence: 99%

Therapeutic Modalities in Diabetic Nephropathy: Standard and Emerging Approaches

et al. 2011

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Diabetes mellitus is the leading cause of end stage renal disease and is responsible for more than 40% of all cases in the United States. Current therapy directed at delaying the progression of diabetic nephropathy includes intensive glycemic and optimal blood pressure control, proteinuria/albuminuria reduction, interruption of the renin-angiotensin-aldosterone system through the use of angiotensin converting enzyme inhibitors and angiotensin type-1 receptor blockers, along with dietary modification and cholesterol lowering agents. However, the renal protection provided by these therapeutic modalities is incomplete. More effective approaches are urgently needed. This review highlights the available standard therapeutic approaches to manage progressive diabetic nephropathy, including markers for early diagnosis of diabetic nephropathy. Furthermore, we will discuss emerging strategies such as PPAR-gamma agonists, Endothelin blockers, vitamin D activation and inflammation modulation. Finally, we will summarize the recommendations of these interventions for the primary care practitioner.

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Effect of Troglitazene on Microalbuminuria in Patients With Incipient Diabetic Nephropathy

Cited by 184 publications

References 13 publications

Rosiglitazone enhances glucose uptake in glomerular podocytes using the glucose transporter GLUT1

Rosiglitazone enhances glucose uptake in glomerular podocytes using the glucose transporter GLUT1

Peroxisome Proliferator-Activated Receptor-γ2 Polymorphism Pro12Ala Is Associated With Nephropathy in Type 2 Diabetes

Therapeutic Modalities in Diabetic Nephropathy: Standard and Emerging Approaches

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