Mechanism of Perturbation of Integrin-Mediated Cell-Matrix Interactions by Reactive Carbonyl Compounds and Its Implication for Pathogenesis of Diabetic Nephropathy

Pedchenko, Vadim; Chetyrkin, Sergei V.; Chuang, Peale; Ham, Amy-Joan L.; Saleem, Moin A.; Mathieson, Peter W.; Hudson, Billy G.; Voziyan, Paul A.

doi:10.2337/diabetes.54.10.2952

Cited by 90 publications

(87 citation statements)

References 70 publications

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“…Other studies have found degeneration of sciatic nerve and retina characteristic of early-stage diabetic neuropathy and retinopathy in this model [14,15]. Increased tissue content of AGEs in diabetes leads to impairment of protein function, linked to vascular cell detachment and anoikis [16,17], oxidative stress [18], low-grade inflammation [18,19] and other cell dysfunctions implicated in the development of microvascular complications [20]. Thiamine and benfotiamine proba- Data are means±SD; units are mmol/mol lysine for FL, CML and CEL and mmol/mol arginine for G-H1, MG-H1 and 3DG-H Rat study group key as in Table 1 *p<0.05, **p<0.01 and ***p<0.001 with respect to normal control † p<0.05, † † p<0.01 † † † p<0.001 with respect to diabetic controls bly decrease AGE and oxidation and nitration adduct formation by increasing transketolase expression and activity in tissues [3,4,21]; this counters metabolic dysfunction and oxidative stress in hyperglycaemia, maintains antioxidant and dicarbonyl-metabolising enzyme activities and thereby prevents protein damage [2].…”

Section: Discussionmentioning

confidence: 70%

Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes

et al. 2010

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Aims/hypothesis The aim of this study was to quantify protein damage by glycation, oxidation and nitration in a rat model of diabetes at the sites of development of microvascular complications, including the effects of thiamine and benfotiamine therapy. Methods Diabetes was induced in male Sprague-Dawley rats by 55 mg/kg streptozotocin and moderated by insulin (2 U twice daily). Diabetic and control rats were given thiamine or benfotiamine (7 or 70 mg kg −1 day −1 ) over 24 weeks. Plasma, urine and tissues were collected and analysed for protein damage by stable isotopic dilution analysis MS. Results There were two-to fourfold increases in fructosyllysine and AGE content of glomerular, retinal, sciatic nerve and plasma protein in diabetes. Increases in AGEs were reversed by thiamine and benfotiamine therapy but increases in fructosyl-lysine were not. Methionine sulfoxide content of plasma protein and 3-nitrotyrosine content of sciatic nerve protein were increased in diabetes. Plasma glycation free adducts were increased up to twofold in diabetes; the increases were reversed by thiamine. Urinary excretion of glycation, oxidation and nitration free adducts was increased by seven-to 27-fold in diabetes. These increases were reversed by thiamine and benfotiamine therapy. Conclusions/interpretation AGEs, particularly argininederived hydroimidazolones, accumulate at sites of microvascular complication development and have markedly increased urinary excretion rates in experimental diabetes. Thiamine and benfotiamine supplementation prevented tissue accumulation and increased urinary excretion of protein glycation, oxidation and nitration adducts. Similar effects may contribute to the reversal of early-stage clinical diabetic nephropathy by thiamine.

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Section: Discussionmentioning

confidence: 70%

Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes

et al. 2010

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“…16,17 More recently, we proposed that perturbation of glomerular cell interactions with the underlying ECM may play an important role in the development of diabetic renal pathology. 18,19 In this context, cell adhesion to collagen IV can be inhibited by MGO-induced noncrosslink modifications of specific arginine residues in the integrin binding sites of this ECM protein. 18 The disruption of these integrin-ECM interactions is important in DN pathogenesis because diabetic mice lacking integrin ␣1␤1, a major collagen IV receptor, develop more severe glomerular scarring than diabetic wild-type mice.…”

mentioning

confidence: 99%

Modification of Collagen IV by Glucose or Methylglyoxal Alters Distinct Mesangial Cell Functions

Pozzi¹,

Zent

Chetyrkin³

et al. 2009

Journal of the American Society of Nephrology

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“…Furthermore, we recently demonstrated that modification of the critical arginine residue within this KRGDS motif by reactive carbonyl compounds inhibited ␣v␤3 integrin-mediated adhesion of podocytes. 23 Possibly, increased levels of carbonyl compounds, known as a "carbonyl stress," may contribute to the perturbation of podocyte-GBM interactions that contribute to diabetic nephropathy. The exposed KRGDS motif in native GBM supports the notion that this mechanism may be operable under diabetic conditions in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…A conditionally immortalized human podocyte cell line 23 was used to determine whether podocytes can adhere to recombinant human ␣1-␣ 6 NC1 monomers. Among these, podocytes only adhered to ␣3 NC1 that contained a KRGDS motif within the collagenous domain adjacent to the NC1 domain of the ␣3 chain of collagen IV (RGD-␣3) ( Figure 2A).…”

Section: Podocyte Adhesion To Recombinant Nc1 Monomers Of Collagen IVmentioning

confidence: 99%

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Human Podocytes Adhere to the KRGDS Motif of the α3α4α5 Collagen IV Network

Borza¹,

Borza²,

Pedchenko³

et al. 2008

Journal of the American Society of Nephrology

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Podocyte adhesion to the glomerular basement membrane is required for proper function of the glomerular filtration barrier. However, the mechanism whereby podocytes adhere to collagen IV networks, a major component of the glomerular basement membrane, is poorly understood. The predominant collagen IV network is composed of triple helical protomers containing the ␣3␣4␣5 chains. The protomers connect via the trimeric noncollagenous (NC1) domains to form hexamers at the interface. Because the NC1 domains of this network can potentially support integrin-dependent cell adhesion, it was determined whether individual NC1 monomers or ␣3␣4␣5 hexamers support podocyte adhesion. It was found that, although human podocytes did not adhere to NC1 domains proper, they did adhere via integrin ␣v␤3 to a KRGDS motif located adjacent to ␣3NC1 domains. Because the KRGDS motif is a site of phosphorylation, its interactions with integrin ␣v␤3 may play a critical role in cell signaling in physiologic and pathologic states.

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Mechanism of Perturbation of Integrin-Mediated Cell-Matrix Interactions by Reactive Carbonyl Compounds and Its Implication for Pathogenesis of Diabetic Nephropathy

Cited by 90 publications

References 70 publications

Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes

Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes

Modification of Collagen IV by Glucose or Methylglyoxal Alters Distinct Mesangial Cell Functions

Human Podocytes Adhere to the KRGDS Motif of the α3α4α5 Collagen IV Network

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