Activation of Tubular Epithelial Cells in Diabetic Nephropathy

Morcos, Michael; Sayed, Ahmed Rabee; Bierhaus, Angelika; Yard, Benito A.; Waldherr, Rüdiger; Merz, Wolfgang E.; Kloeting, I.; Schleicher, Erwin; Mentz, Stefani; Baki, Randa F. Abd el; Tritschler, Hans; Kasper, Michael; Schwenger, Vedat; Hamann, Andreas; Dugi, Klaus A.; Schmidt, Annemarie; Stern, David M.; Ziegler, Reinhard; Haering, Hans U.; Andrassy, Martin; Woude, Fokko van der; Nawroth, Peter P.

doi:10.2337/diabetes.51.12.3532

Cited by 144 publications

(130 citation statements)

References 116 publications

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“…However, this is the first time that an increase in all three AGE subtypes has been demonstrated in ZDF rats, an increase that was suppressed simultaneously by drug intervention. In patients with diabetic nephropathy, urinary excretion of CML is reduced, and insufficient clearance may result in increased serum AGE concentrations as well as tissue accumulation of AGEs [26][27][28][29]. This is further supported by the fact that the AGE inhibitor aminoguanidine improved renal function in diabetic nephropathy, reduced tissue AGE deposits [30][31][32] and increased urinary excretion of dietary AGEs [33].…”

Section: Discussionmentioning

confidence: 91%

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

Wihler¹,

Schäfer²,

Schmid³

et al. 2005

Diabetologia

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Aims/hypothesis: Renal accumulation of AGEs may contribute to the progression of diabetic nephropathy. We evaluated the effect of ramipril (a pure ACE inhibitor) and AVE7688 (a dual inhibitor of ACE and neutral endopeptidase) on renal accumulation of the advanced glycation end-product (AGE) 3-deoxyglucosone-imidazolone, carboxymethyllysine (CML) and pentosidine, and on clearance of CML in type 2 diabetes. Methods: Male Zucker diabetic fatty rats (ZDF, Gmi-fa/fa) rats were treated from age 10 to 37 weeks with ramipril (1 mg·kg −1 ·day −1 ), AVE7688 (45 mg·kg −1 ·day −1 ) or without drug. Ramipril and AVE7688 reduced albuminuria by 30 and 90%, respectively. Results: ZDF rats showed increased renal accumulation of the AGE subtypes 3-deoxyglucosone-imidazolone, pentosidine and CML by about 40, 55 and 55%, respectively compared with heterozygous, non-diabetic control animals at the age of 37 weeks. AVE7688 but not ramipril attenuated the renal accumulation of 3-deoxyglucosone-imidazolone, pentosidine and CML and improved CML clearance in ZDF rats. During glycation reactions in vitro, AVE7688 also demonstrated potent chelating activity and inhibited metal-catalysed formation of pentosidine and CML. Conclusions/interpretation: Improved AGE clearance and direct inhibition of AGE formation by chelation may contribute to reduced accumulation of renal AGEs and to the nephroprotective effects of vasopeptidase inhibition in type 2 diabetes.

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Section: Discussionmentioning

confidence: 91%

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

Wihler¹,

Schäfer²,

Schmid³

et al. 2005

Diabetologia

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“…In this way, tubulointerstitial inflammation deteriorates renal function over time. Previous studies have shown that renal function in type 2 diabetes correlates better with tubular changes than with glomerular pathology (2,3). Further studies of tubulointerstitial disease in addition to glomerular injury in diabetes may provide additional insight into the pathogenesis of diabetic nephropathy and lead to the identification of targets for therapeutic intervention (17).…”

Section: Discussionmentioning

confidence: 99%

Effect of Pitavastatin on Urinary Liver-Type Fatty Acid–Binding Protein Levels in Patients With Early Diabetic Nephropathy

Nakamura

Sugaya²,

Kawagoe

et al. 2005

Diabetes Care

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OBJECTIVE -Liver-type fatty acid-binding protein (L-FABP) is expressed in renal proximal tubules and is reported to be a useful marker for progression of chronic glomerulonephritis. The aim of this study was to determine whether urinary L-FABP levels are altered at various stages of diabetic nephropathy and whether pitavastatin affects urinary L-FABP levels in early diabetic nephropathy.RESEARCH DESIGN AND METHODS -Fifty-eight patients with type 2 diabetes (34 men and 24 women, median age 52 years) and 20 healthy, age-matched subjects (group E) were recruited for the study. The diabetic patients included 12 patients without nephropathy (group A), 20 patients with microalbuminuria (group B), 14 patients with macroalbuminuria and normal renal function (group C), and 12 patients with chronic renal failure but not undergoing hemodialysis (blood creatinine Ͼ1.2 mg/dl; mean 2.5 mg/dl, group D). Twenty group B patients were randomly assigned to receive 1 mg/day pitavastatin (10 patients, group B1) or placebo (10 patients, group B2). Treatment was continued for 12 months. Urinary L-FABP levels were measured by enzyme-linked immunosorbent assay. Urinary 8-hydroxydeoxyguanosine and serum free fatty acids (FFAs) were also measured in group B.RESULTS -Urinary L-FABP levels in groups A-D were 6.2 Ϯ 4.6 g/g creatinine, 19.6 Ϯ 13.5 g/g creatinine, 26.8 Ϯ 20.4 g/g creatinine, and 52.4 Ϯ 46.8 g/g creatinine, respectively. Urinary L-FABP levels in groups B-D were significantly higher than those in healthy subjects (group E, 5.8 Ϯ 4.0 g/g creatinine) (group B, P Ͻ 0.05; group C, P Ͻ 0.01; group D, P Ͻ 0.01). In group B1, urinary albumin excretion (UAE) and urinary L-FABP levels were decreased after pitavastatin treatment (UAE before, 110 Ϯ 74 g/min; 6 months, 88 Ϯ 60 g/min, P Ͻ 0.05; 12 months, 58 Ϯ 32 g/min, P Ͻ 0.01; L-FABP before, 18.6 Ϯ 12.5 g/g creatinine; 6 months, 12.2 Ϯ 8.8 g/g creatinine, P Ͻ 0.05; 12 months, 8.8 Ϯ 6.4 g/g creatinine, P Ͻ 0.01). In group B2, UAE and L-FABP levels showed little change during the experimental period. In group B1, urinary 8-hydroxydeoxyguanosine was decreased 12 months after pitavastatin treatment (before 32.5 Ϯ 19.5 ng/mg creatinine, after 18.8 Ϯ 14.5 ng/mg creatinine, P Ͻ 0.01), but in group B2, these showed little difference during the experimental period. In both groups B1 and B2, serum FFAs showed little difference during the experimental period.CONCLUSIONS -Urinary L-FABP levels appear to be associated with the progression of diabetic nephropathy, and pitavastatin may be effective in ameliorating tubulointerstitial damage in early diabetic nephropathy. Diabetes Care 28:2728 -2732, 2005D iabetes-associated nephropathy is the leading cause of end-stage renal disease. The pathogenesis of diabetic nephropathy is multifactorial, and the precise mechanisms are unclear. It is now widely accepted that the rate of functional deterioration correlates with the degree of renal tubulointerstitial fibrosis (1). Epithelial cells of the proximal tubules play a major role in orchestrating events in the...

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“…Where indicated, cells were pretreated for 1 h with 50 M PD98059, 30 min with 50 nM wortmannin, 2 h with 5 M PP1, or 30 min with 10 M U73122 or 5 M U73343 before the incubation with HGA. Where indicated, 50 g/ml of soluble RAGE (sRAGE) were added together with HGA for the appropriated times (32).…”

Section: Methodsmentioning

confidence: 99%

In Skeletal Muscle Advanced Glycation End Products (AGEs) Inhibit Insulin Action and Induce the Formation of Multimolecular Complexes Including the Receptor for AGEs

Cassese

Esposito

Fiory

et al. 2008

Journal of Biological Chemistry

105

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Chronic hyperglycemia promotes insulin resistance at least in part by increasing the formation of advanced glycation end products (AGEs). We have previously shown that in L6 myotubes human glycated albumin (HGA) induces insulin resistance by activating protein kinase C␣ (PKC␣). Here we show that HGA-induced PKC␣ activation is mediated by Src. Coprecipitation experiments showed that Src interacts with both the receptor for AGE (RAGE) and PKC␣ in HGA-treated L6 cells. A direct interaction of PKC␣ with Src and insulin receptor substrate-1 (IRS-1) has also been detected. In addition, silencing of IRS-1 expression abolished HGA-induced RAGE-PKC␣ co-precipitation. AGEs were able to induce insulin resistance also in vivo, as insulin tolerance tests revealed a significant impairment of insulin sensitivity in C57/BL6 mice fed a high AGEs diet (HAD). In tibialis muscle of HAD-fed mice, insulin-induced glucose uptake and protein kinase B phosphorylation were reduced. This was paralleled by a 2.5-fold increase in PKC␣ activity. Similarly to in vitro observations, Src phosphorylation was increased in tibialis muscle of HAD-fed mice, and co-precipitation experiments showed that Src interacts with both RAGE and PKC␣. These results indicate that AGEs impairment of insulin action in the muscle might be mediated by the formation of a multimolecular complex including RAGE/IRS-1/Src and PKC␣.

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Activation of Tubular Epithelial Cells in Diabetic Nephropathy

Cited by 144 publications

References 116 publications

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

Effect of Pitavastatin on Urinary Liver-Type Fatty Acid–Binding Protein Levels in Patients With Early Diabetic Nephropathy

In Skeletal Muscle Advanced Glycation End Products (AGEs) Inhibit Insulin Action and Induce the Formation of Multimolecular Complexes Including the Receptor for AGEs

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