The Experts below are selected from a list of 2424 Experts worldwide ranked by ideXlab platform
Richard E. Gilbert - One of the best experts on this subject based on the ideXlab platform.
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aliskiren a novel renin inhibitor is renoprotective in a model of advanced Diabetic Nephropathy in rats
Diabetologia, 2007Co-Authors: Darren J. Kelly, Richard E. Gilbert, Yuan Zhang, Gordon W Moe, G NaikAbstract:Aims/hypothesis Blockade of the renin–angiotensin system (RAS) with either ACE inhibitors or angiotensin receptor blocker is a key therapeutic strategy in slowing progression of Diabetic Nephropathy. Interruption of the RAS may also be achieved by blocking the activity of renin, the rate-limiting step in angiotensin II biosynthesis. However, it is not known whether drugs in this class also reduce the structural and functional manifestations of Diabetic Nephropathy. Methods Using Diabetic transgenic (mRen-2)27 rats, a rodent model of advanced Diabetic Nephropathy, we compared the efficacy of the renin inhibitor, aliskiren (10 mg kg �1 day �1 by osmotic mini-pump), with the ACE inhibitor, perindopril (0.2 mg kg �1 day �1 in drinking water), over a 16 week period. Results Both perindopril and aliskiren reduced blood pressure, albuminuria and structural injury in Experimental Diabetic Nephropathy, although not to the same extent. Aliskiren, at the dose used, did not reduce systemic blood pressure as much as perindopril, but both compounds were equally effective in reducing albuminuria and glomerulosclerosis in Diabetic animals. The magnitude of interstitial fibrosis was attenuated to a greater degree by aliskiren than by perindopril. Conclusions/interpretation These findings suggest that therapies aimed at different targets within the RAS may not have identical effects in attenuating structural injury in Experimental Diabetic Nephropathy.
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protein kinase c β inhibition attenuates the progression of Experimental Diabetic Nephropathy in the presence of continued hypertension
Diabetes, 2003Co-Authors: Darren J. Kelly, Richard E. Gilbert, Yuan Zhang, Claire Hepper, Renae M Gow, Kassie Ann Jaworski, Bruce E Kemp, Jennifer L WilkinsonberkaAbstract:In addition to hyperglycemia, hypertension and the renin-angiotensin system have been consistently implicated in the pathogenesis of Diabetic Nephropathy. Each of these pathogenetic factors may induce changes in cellular function by a common intracellular signaling pathway, the activation of protein kinase C (PKC) beta. The present study thus sought to determine the in vivo effect of PKC beta inhibition in Experimental Diabetic Nephropathy in the setting of continued hyperglycemia, hypertension, and activation of the RAS. Studies were conducted in the (mRen-2)27 rat, a rodent that is transgenic for the entire mouse renin gene (Ren-2) and develops many of the structural, functional, and molecular characteristics of human Diabetic Nephropathy when Experimental diabetes is induced with streptozotocin (STZ). Six-week-old female Ren-2 rats received an injection of STZ or vehicle and were maintained for 6 months. Within 24 h, Diabetic rats were further randomized to receive treatment with the specific PKC beta inhibitor, LY333531, admixed in diet (10 mg x kg(-1) x d(-1)) or no treatment (n = 8/group). Diabetic rats developed albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis with a concomitant increase in transforming growth factor-beta (TGF-beta). Western blot analysis demonstrated increased PKC beta in Diabetic animals, localized by immunofluorescence to the glomerular mesangium. In vivo inhibition of PKC beta with LY333531 led to a reduction in albuminuria, structural injury, and TGF-beta expression, despite continued hypertension and hyperglycemia.
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protein kinase c β inhibition attenuates the progression of Experimental Diabetic Nephropathy in the presence of continued hypertension
Diabetes, 2003Co-Authors: Darren J. Kelly, Richard E. Gilbert, Yuan Zhang, Claire Hepper, Renae M Gow, Kassie Ann Jaworski, Bruce E Kemp, Jennifer L WilkinsonberkaAbstract:In addition to hyperglycemia, hypertension and the renin-angiotensin system have been consistently implicated in the pathogenesis of Diabetic Nephropathy. Each of these pathogenetic factors may induce changes in cellular function by a common intracellular signaling pathway, the activation of protein kinase C (PKC) β. The present study thus sought to determine the in vivo effect of PKC β inhibition in Experimental Diabetic Nephropathy in the setting of continued hyperglycemia, hypertension, and activation of the RAS. Studies were conducted in the (mRen-2)27 rat, a rodent that is transgenic for the entire mouse renin gene (Ren-2) and develops many of the structural, functional, and molecular characteristics of human Diabetic Nephropathy when Experimental diabetes is induced with streptozotocin (STZ). Six-week-old female Ren-2 rats received an injection of STZ or vehicle and were maintained for 6 months. Within 24 h, Diabetic rats were further randomized to receive treatment with the specific PKC β inhibitor, LY333531, admixed in diet (10 mg · kg−1 · d−1) or no treatment (n = 8/group). Diabetic rats developed albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis with a concomitant increase in transforming growth factor-β (TGF-β). Western blot analysis demonstrated increased PKC β in Diabetic animals, localized by immunofluorescence to the glomerular mesangium. In vivo inhibition of PKC β with LY333531 led to a reduction in albuminuria, structural injury, and TGF-β expression, despite continued hypertension and hyperglycemia.
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Expression of the slit‐diaphragm protein, nephrin, in Experimental Diabetic Nephropathy: differing effects of anti‐proteinuric therapies
Nephrology dialysis transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2002Co-Authors: Darren J. Kelly, George Jerums, Sianna Panagiotopoulos, Alison J Cox, Petri Aaltonen, Jon R. Rumble, Robyn G Langham, Harry Holthöfer, Richard E. GilbertAbstract:Background. Mutations in the gene coding for the podocyte slit-pore membrane protein, nephrin, are responsible for the Finnish-type congenital nephrotic syndrome. The present study sought to examine whether nephrin expression may also be altered in Experimental diabetes, and how such changes related to the development of proteinuria. In addition, the study also sought to examine nephrin expression in animals treated with different anti-proteinuric therapies. Methods. Nephrin gene expression and localization were examined in rats with streptozotocin-induced diabetes at 6 months duration (proteinuric phase) and at 7 days (pre-proteinuric phase). In addition, the effects of anti-proteinuric drug therapies were also assessed in long-term Diabetic rats, treated with either the angiotensin-converting enzyme inhibitor perindopril, or the blocker of advanced glycation end-product formation, aminoguanidine. Nephrin expression was determined using quantitative real-time PCR and in situ hybridization. Results. When compared with control animals, nephrin expression was reduced in the late proteinuric phase (45% reductionvs controls,P-0.01) but not in the early, pre-proteinuric phase of Experimental Diabetic Nephropathy. While ACE inhibition and aminoguanidine both reduced proteinuria, only the former attenuated the diabetes-associated reduction in nephrin expression. Conclusions. These findings suggests that reduction in nephrin may be a determinant of glomerular hyperpermeability in Diabetic Nephropathy. Attenuation of these changes with ACE inhibition suggest that this mechanism may contribute to the anti-proteinuric effects of this, but not all classes of drug which reduce urinary protein in Diabetic Nephropathy.
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expression of the slit diaphragm protein nephrin in Experimental Diabetic Nephropathy differing effects of anti proteinuric therapies
Nephrology Dialysis Transplantation, 2002Co-Authors: Darren J. Kelly, George Jerums, Sianna Panagiotopoulos, Alison J Cox, Petri Aaltonen, Jon R. Rumble, Robyn G Langham, Harry Holthöfer, Richard E. GilbertAbstract:Background. Mutations in the gene coding for the podocyte slit-pore membrane protein, nephrin, are responsible for the Finnish-type congenital nephrotic syndrome. The present study sought to examine whether nephrin expression may also be altered in Experimental diabetes, and how such changes related to the development of proteinuria. In addition, the study also sought to examine nephrin expression in animals treated with different anti-proteinuric therapies. Methods. Nephrin gene expression and localization were examined in rats with streptozotocin-induced diabetes at 6 months duration (proteinuric phase) and at 7 days (pre-proteinuric phase). In addition, the effects of anti-proteinuric drug therapies were also assessed in long-term Diabetic rats, treated with either the angiotensin-converting enzyme inhibitor perindopril, or the blocker of advanced glycation end-product formation, aminoguanidine. Nephrin expression was determined using quantitative real-time PCR and in situ hybridization. Results. When compared with control animals, nephrin expression was reduced in the late proteinuric phase (45% reductionvs controls,P-0.01) but not in the early, pre-proteinuric phase of Experimental Diabetic Nephropathy. While ACE inhibition and aminoguanidine both reduced proteinuria, only the former attenuated the diabetes-associated reduction in nephrin expression. Conclusions. These findings suggests that reduction in nephrin may be a determinant of glomerular hyperpermeability in Diabetic Nephropathy. Attenuation of these changes with ACE inhibition suggest that this mechanism may contribute to the anti-proteinuric effects of this, but not all classes of drug which reduce urinary protein in Diabetic Nephropathy.
Darren J. Kelly - One of the best experts on this subject based on the ideXlab platform.
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aliskiren a novel renin inhibitor is renoprotective in a model of advanced Diabetic Nephropathy in rats
Diabetologia, 2007Co-Authors: Darren J. Kelly, Richard E. Gilbert, Yuan Zhang, Gordon W Moe, G NaikAbstract:Aims/hypothesis Blockade of the renin–angiotensin system (RAS) with either ACE inhibitors or angiotensin receptor blocker is a key therapeutic strategy in slowing progression of Diabetic Nephropathy. Interruption of the RAS may also be achieved by blocking the activity of renin, the rate-limiting step in angiotensin II biosynthesis. However, it is not known whether drugs in this class also reduce the structural and functional manifestations of Diabetic Nephropathy. Methods Using Diabetic transgenic (mRen-2)27 rats, a rodent model of advanced Diabetic Nephropathy, we compared the efficacy of the renin inhibitor, aliskiren (10 mg kg �1 day �1 by osmotic mini-pump), with the ACE inhibitor, perindopril (0.2 mg kg �1 day �1 in drinking water), over a 16 week period. Results Both perindopril and aliskiren reduced blood pressure, albuminuria and structural injury in Experimental Diabetic Nephropathy, although not to the same extent. Aliskiren, at the dose used, did not reduce systemic blood pressure as much as perindopril, but both compounds were equally effective in reducing albuminuria and glomerulosclerosis in Diabetic animals. The magnitude of interstitial fibrosis was attenuated to a greater degree by aliskiren than by perindopril. Conclusions/interpretation These findings suggest that therapies aimed at different targets within the RAS may not have identical effects in attenuating structural injury in Experimental Diabetic Nephropathy.
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protein kinase c β inhibition attenuates the progression of Experimental Diabetic Nephropathy in the presence of continued hypertension
Diabetes, 2003Co-Authors: Darren J. Kelly, Richard E. Gilbert, Yuan Zhang, Claire Hepper, Renae M Gow, Kassie Ann Jaworski, Bruce E Kemp, Jennifer L WilkinsonberkaAbstract:In addition to hyperglycemia, hypertension and the renin-angiotensin system have been consistently implicated in the pathogenesis of Diabetic Nephropathy. Each of these pathogenetic factors may induce changes in cellular function by a common intracellular signaling pathway, the activation of protein kinase C (PKC) β. The present study thus sought to determine the in vivo effect of PKC β inhibition in Experimental Diabetic Nephropathy in the setting of continued hyperglycemia, hypertension, and activation of the RAS. Studies were conducted in the (mRen-2)27 rat, a rodent that is transgenic for the entire mouse renin gene (Ren-2) and develops many of the structural, functional, and molecular characteristics of human Diabetic Nephropathy when Experimental diabetes is induced with streptozotocin (STZ). Six-week-old female Ren-2 rats received an injection of STZ or vehicle and were maintained for 6 months. Within 24 h, Diabetic rats were further randomized to receive treatment with the specific PKC β inhibitor, LY333531, admixed in diet (10 mg · kg−1 · d−1) or no treatment (n = 8/group). Diabetic rats developed albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis with a concomitant increase in transforming growth factor-β (TGF-β). Western blot analysis demonstrated increased PKC β in Diabetic animals, localized by immunofluorescence to the glomerular mesangium. In vivo inhibition of PKC β with LY333531 led to a reduction in albuminuria, structural injury, and TGF-β expression, despite continued hypertension and hyperglycemia.
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protein kinase c β inhibition attenuates the progression of Experimental Diabetic Nephropathy in the presence of continued hypertension
Diabetes, 2003Co-Authors: Darren J. Kelly, Richard E. Gilbert, Yuan Zhang, Claire Hepper, Renae M Gow, Kassie Ann Jaworski, Bruce E Kemp, Jennifer L WilkinsonberkaAbstract:In addition to hyperglycemia, hypertension and the renin-angiotensin system have been consistently implicated in the pathogenesis of Diabetic Nephropathy. Each of these pathogenetic factors may induce changes in cellular function by a common intracellular signaling pathway, the activation of protein kinase C (PKC) beta. The present study thus sought to determine the in vivo effect of PKC beta inhibition in Experimental Diabetic Nephropathy in the setting of continued hyperglycemia, hypertension, and activation of the RAS. Studies were conducted in the (mRen-2)27 rat, a rodent that is transgenic for the entire mouse renin gene (Ren-2) and develops many of the structural, functional, and molecular characteristics of human Diabetic Nephropathy when Experimental diabetes is induced with streptozotocin (STZ). Six-week-old female Ren-2 rats received an injection of STZ or vehicle and were maintained for 6 months. Within 24 h, Diabetic rats were further randomized to receive treatment with the specific PKC beta inhibitor, LY333531, admixed in diet (10 mg x kg(-1) x d(-1)) or no treatment (n = 8/group). Diabetic rats developed albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis with a concomitant increase in transforming growth factor-beta (TGF-beta). Western blot analysis demonstrated increased PKC beta in Diabetic animals, localized by immunofluorescence to the glomerular mesangium. In vivo inhibition of PKC beta with LY333531 led to a reduction in albuminuria, structural injury, and TGF-beta expression, despite continued hypertension and hyperglycemia.
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Expression of the slit‐diaphragm protein, nephrin, in Experimental Diabetic Nephropathy: differing effects of anti‐proteinuric therapies
Nephrology dialysis transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2002Co-Authors: Darren J. Kelly, George Jerums, Sianna Panagiotopoulos, Alison J Cox, Petri Aaltonen, Jon R. Rumble, Robyn G Langham, Harry Holthöfer, Richard E. GilbertAbstract:Background. Mutations in the gene coding for the podocyte slit-pore membrane protein, nephrin, are responsible for the Finnish-type congenital nephrotic syndrome. The present study sought to examine whether nephrin expression may also be altered in Experimental diabetes, and how such changes related to the development of proteinuria. In addition, the study also sought to examine nephrin expression in animals treated with different anti-proteinuric therapies. Methods. Nephrin gene expression and localization were examined in rats with streptozotocin-induced diabetes at 6 months duration (proteinuric phase) and at 7 days (pre-proteinuric phase). In addition, the effects of anti-proteinuric drug therapies were also assessed in long-term Diabetic rats, treated with either the angiotensin-converting enzyme inhibitor perindopril, or the blocker of advanced glycation end-product formation, aminoguanidine. Nephrin expression was determined using quantitative real-time PCR and in situ hybridization. Results. When compared with control animals, nephrin expression was reduced in the late proteinuric phase (45% reductionvs controls,P-0.01) but not in the early, pre-proteinuric phase of Experimental Diabetic Nephropathy. While ACE inhibition and aminoguanidine both reduced proteinuria, only the former attenuated the diabetes-associated reduction in nephrin expression. Conclusions. These findings suggests that reduction in nephrin may be a determinant of glomerular hyperpermeability in Diabetic Nephropathy. Attenuation of these changes with ACE inhibition suggest that this mechanism may contribute to the anti-proteinuric effects of this, but not all classes of drug which reduce urinary protein in Diabetic Nephropathy.
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expression of the slit diaphragm protein nephrin in Experimental Diabetic Nephropathy differing effects of anti proteinuric therapies
Nephrology Dialysis Transplantation, 2002Co-Authors: Darren J. Kelly, George Jerums, Sianna Panagiotopoulos, Alison J Cox, Petri Aaltonen, Jon R. Rumble, Robyn G Langham, Harry Holthöfer, Richard E. GilbertAbstract:Background. Mutations in the gene coding for the podocyte slit-pore membrane protein, nephrin, are responsible for the Finnish-type congenital nephrotic syndrome. The present study sought to examine whether nephrin expression may also be altered in Experimental diabetes, and how such changes related to the development of proteinuria. In addition, the study also sought to examine nephrin expression in animals treated with different anti-proteinuric therapies. Methods. Nephrin gene expression and localization were examined in rats with streptozotocin-induced diabetes at 6 months duration (proteinuric phase) and at 7 days (pre-proteinuric phase). In addition, the effects of anti-proteinuric drug therapies were also assessed in long-term Diabetic rats, treated with either the angiotensin-converting enzyme inhibitor perindopril, or the blocker of advanced glycation end-product formation, aminoguanidine. Nephrin expression was determined using quantitative real-time PCR and in situ hybridization. Results. When compared with control animals, nephrin expression was reduced in the late proteinuric phase (45% reductionvs controls,P-0.01) but not in the early, pre-proteinuric phase of Experimental Diabetic Nephropathy. While ACE inhibition and aminoguanidine both reduced proteinuria, only the former attenuated the diabetes-associated reduction in nephrin expression. Conclusions. These findings suggests that reduction in nephrin may be a determinant of glomerular hyperpermeability in Diabetic Nephropathy. Attenuation of these changes with ACE inhibition suggest that this mechanism may contribute to the anti-proteinuric effects of this, but not all classes of drug which reduce urinary protein in Diabetic Nephropathy.
Mark E. Cooper - One of the best experts on this subject based on the ideXlab platform.
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targeting the cda1 cda1bp1 axis retards renal fibrosis in Experimental Diabetic Nephropathy
Diabetes, 2019Co-Authors: Zhonglin Chai, Aozhi Dai, Pacific Huynh, Frank Koentgen, Guy Y. Krippner, Shuting Ren, Mark E. CooperAbstract:Targeting cell division autoantigen 1 (CDA1) is postulated to attenuate the profibrotic actions of transforming growth factor-β in Diabetic Nephropathy. This study has identified a regulatory protein for CDA1 and has then used genetic and pharmacological approaches to test in vivo whether strategies to target this pathway would lead to reduced renal injury. A novel protein, named CDA1BP1 (CDA1 binding protein 1), was identified as critical in regulating the profibrotic activity of CDA1. Genetic deletion of CDA1BP1 attenuated key parameters of renal fibrosis in Diabetic mice. Furthermore, a series of short synthetic CDA1BP1 peptides competitively inhibited CDA1-CDA1BP1 binding in vitro with a hybrid peptide, CHA-050, containing a 12mer CDA1BP1 peptide and a previously known "cell-penetrating peptide," dose-dependently reducing expression of collagens I and III in HK-2 cells. In vivo, a d-amino acid retro-inverso peptide, CHA-061, significantly attenuated diabetes-associated increases in the renal expression of genes involved in fibrotic and proinflammatory pathways. In a delayed intervention study, CHA-061 treatment reversed diabetes-associated molecular and pathological changes within the kidney. Specifically, CHA-061 significantly attenuated renal extracellular matrix accumulation and glomerular injury. Taken together, targeting the CDA1/CDA1BP1 axis is a safe, efficacious, and feasible approach to retard Experimental Diabetic Nephropathy.
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Targeting the CDA1/CDA1BP1 Axis Retards Renal Fibrosis in Experimental Diabetic Nephropathy
Diabetes, 2018Co-Authors: Zhonglin Chai, Aozhi Dai, Pacific Huynh, Frank Koentgen, Guy Y. Krippner, Shuting Ren, Mark E. CooperAbstract:Targeting cell division autoantigen 1 (CDA1) is postulated to attenuate the profibrotic actions of transforming growth factor-β in Diabetic Nephropathy. This study has identified a regulatory protein for CDA1 and has then used genetic and pharmacological approaches to test in vivo whether strategies to target this pathway would lead to reduced renal injury. A novel protein, named CDA1BP1 (CDA1 binding protein 1), was identified as critical in regulating the profibrotic activity of CDA1. Genetic deletion of CDA1BP1 attenuated key parameters of renal fibrosis in Diabetic mice. Furthermore, a series of short synthetic CDA1BP1 peptides competitively inhibited CDA1-CDA1BP1 binding in vitro with a hybrid peptide, CHA-050, containing a 12mer CDA1BP1 peptide and a previously known "cell-penetrating peptide," dose-dependently reducing expression of collagens I and III in HK-2 cells. In vivo, a d-amino acid retro-inverso peptide, CHA-061, significantly attenuated diabetes-associated increases in the renal expression of genes involved in fibrotic and proinflammatory pathways. In a delayed intervention study, CHA-061 treatment reversed diabetes-associated molecular and pathological changes within the kidney. Specifically, CHA-061 significantly attenuated renal extracellular matrix accumulation and glomerular injury. Taken together, targeting the CDA1/CDA1BP1 axis is a safe, efficacious, and feasible approach to retard Experimental Diabetic Nephropathy.
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reduction of the accumulation of advanced glycation end products by ace inhibition in Experimental Diabetic Nephropathy
Diabetes, 2002Co-Authors: Josephine M Forbes, Mark E. Cooper, George Jerums, Vicki Thallas, Wendy C Burns, Merlin C Thomas, Gail C Brammar, Sharon L Grant, Louise M Burrell, Tanya M OsickaAbstract:The effect of ACE inhibition on the formation of advanced glycation end products (AGEs) and oxidative stress was explored. Streptozocin-induced Diabetic animals were randomized to no treatment, the ACE inhibitor ramipril (3 mg/l), or the AGE formation inhibitor aminoguanidine (1 g/l) and followed for 12 weeks. Control groups were followed concurrently. Renal AGE accumulation, as determined by immunohistochemistry and both serum and renal fluorescence, were increased in Diabetic animals. This was attenuated by both ramipril and aminoguanidine to a similar degree. Nitrotyrosine, a marker of protein oxidation, also followed a similar pattern. The receptor for AGEs, gene expression of the membrane-bound NADPH oxidase subunit gp91phox, and nuclear transcription factor-κB were all increased by diabetes but remained unaffected by either treatment regimen. Two other AGE receptors, AGE R2 and AGE R3, remained unchanged for the duration of the study. The present study has identified a relationship between the renin-angiotensin system and the accumulation of AGEs in Experimental Diabetic Nephropathy that may be linked through oxidative stress
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Reduction of the Accumulation of Advanced Glycation End Products by ACE Inhibition in Experimental Diabetic Nephropathy
Diabetes, 2002Co-Authors: Josephine M Forbes, Mark E. Cooper, Vicki Thallas, Wendy C Burns, Merlin C Thomas, Gail C Brammar, Sharon L Grant, Louise M Burrell, Fiona T.h. Lee, George JerumsAbstract:The effect of ACE inhibition on the formation of advanced glycation end products (AGEs) and oxidative stress was explored. Streptozocin-induced Diabetic animals were randomized to no treatment, the ACE inhibitor ramipril (3 mg/l), or the AGE formation inhibitor aminoguanidine (1 g/l) and followed for 12 weeks. Control groups were followed concurrently. Renal AGE accumulation, as determined by immunohistochemistry and both serum and renal fluorescence, were increased in Diabetic animals. This was attenuated by both ramipril and aminoguanidine to a similar degree. Nitrotyrosine, a marker of protein oxidation, also followed a similar pattern. The receptor for AGEs, gene expression of the membrane-bound NADPH oxidase subunit gp91phox, and nuclear transcription factor-kappaB were all increased by diabetes but remained unaffected by either treatment regimen. Two other AGE receptors, AGE R2 and AGE R3, remained unchanged for the duration of the study. The present study has identified a relationship between the renin-angiotensin system and the accumulation of AGEs in Experimental Diabetic Nephropathy that may be linked through oxidative stress
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Interaction of metabolic and haemodynamic factors in mediating Experimental Diabetic Nephropathy.
Diabetologia, 2001Co-Authors: Mark E. CooperAbstract:Diabetic Nephropathy seems to occur as a result of an interaction of metabolic and haemodynamic factors. Glucose dependent pathways are activated within the Diabetic kidney. These include increased oxidative stress, renal polyol formation and accumulation of advanced glycated end-products. Haemodynamic factors are also implicated in the pathogenesis of Diabetic Nephropathy and include increased systemic and intraglomerular pressure and activation of various vasoactive hormone pathways including the renin-angiotensin system and endothelin. These haemodynamic pathways, independently and with metabolic pathways, activate intracellular second messengers such as protein kinase C and MAP kinase, nuclear transcription factors such as NF-kappaB and various growth factors such as the prosclerotic cytokine, TGF-beta and the angiogenic, permeability enhancing growth factor, VEGF. These pathways ultimately lead to increased renal albumin permeability and extracellular matrix accumulation which results in increasing proteinuria, glomerulosclerosis and tubulointerstitial fibrosis. Therapeutic strategies involved in the management and prevention of Diabetic Nephropathy include currently available treatments such as intensified glycaemic control and antihypertensive agents, particularly those which interrupt the renin-angiotensin system. More novel strategies to influence vasoactive hormone action or to inhibit various metabolic pathways such as inhibitors of advanced glycation, specific protein kinase C isoforms and aldose reductase are at present under Experimental and clinical investigation. It is predicted that multiple therapies will be required to reduce the progression of Diabetic Nephropathy.
George Jerums - One of the best experts on this subject based on the ideXlab platform.
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reduction of the accumulation of advanced glycation end products by ace inhibition in Experimental Diabetic Nephropathy
Diabetes, 2002Co-Authors: Josephine M Forbes, Mark E. Cooper, George Jerums, Vicki Thallas, Wendy C Burns, Merlin C Thomas, Gail C Brammar, Sharon L Grant, Louise M Burrell, Tanya M OsickaAbstract:The effect of ACE inhibition on the formation of advanced glycation end products (AGEs) and oxidative stress was explored. Streptozocin-induced Diabetic animals were randomized to no treatment, the ACE inhibitor ramipril (3 mg/l), or the AGE formation inhibitor aminoguanidine (1 g/l) and followed for 12 weeks. Control groups were followed concurrently. Renal AGE accumulation, as determined by immunohistochemistry and both serum and renal fluorescence, were increased in Diabetic animals. This was attenuated by both ramipril and aminoguanidine to a similar degree. Nitrotyrosine, a marker of protein oxidation, also followed a similar pattern. The receptor for AGEs, gene expression of the membrane-bound NADPH oxidase subunit gp91phox, and nuclear transcription factor-κB were all increased by diabetes but remained unaffected by either treatment regimen. Two other AGE receptors, AGE R2 and AGE R3, remained unchanged for the duration of the study. The present study has identified a relationship between the renin-angiotensin system and the accumulation of AGEs in Experimental Diabetic Nephropathy that may be linked through oxidative stress
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Reduction of the Accumulation of Advanced Glycation End Products by ACE Inhibition in Experimental Diabetic Nephropathy
Diabetes, 2002Co-Authors: Josephine M Forbes, Mark E. Cooper, Vicki Thallas, Wendy C Burns, Merlin C Thomas, Gail C Brammar, Sharon L Grant, Louise M Burrell, Fiona T.h. Lee, George JerumsAbstract:The effect of ACE inhibition on the formation of advanced glycation end products (AGEs) and oxidative stress was explored. Streptozocin-induced Diabetic animals were randomized to no treatment, the ACE inhibitor ramipril (3 mg/l), or the AGE formation inhibitor aminoguanidine (1 g/l) and followed for 12 weeks. Control groups were followed concurrently. Renal AGE accumulation, as determined by immunohistochemistry and both serum and renal fluorescence, were increased in Diabetic animals. This was attenuated by both ramipril and aminoguanidine to a similar degree. Nitrotyrosine, a marker of protein oxidation, also followed a similar pattern. The receptor for AGEs, gene expression of the membrane-bound NADPH oxidase subunit gp91phox, and nuclear transcription factor-kappaB were all increased by diabetes but remained unaffected by either treatment regimen. Two other AGE receptors, AGE R2 and AGE R3, remained unchanged for the duration of the study. The present study has identified a relationship between the renin-angiotensin system and the accumulation of AGEs in Experimental Diabetic Nephropathy that may be linked through oxidative stress
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Expression of the slit‐diaphragm protein, nephrin, in Experimental Diabetic Nephropathy: differing effects of anti‐proteinuric therapies
Nephrology dialysis transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2002Co-Authors: Darren J. Kelly, George Jerums, Sianna Panagiotopoulos, Alison J Cox, Petri Aaltonen, Jon R. Rumble, Robyn G Langham, Harry Holthöfer, Richard E. GilbertAbstract:Background. Mutations in the gene coding for the podocyte slit-pore membrane protein, nephrin, are responsible for the Finnish-type congenital nephrotic syndrome. The present study sought to examine whether nephrin expression may also be altered in Experimental diabetes, and how such changes related to the development of proteinuria. In addition, the study also sought to examine nephrin expression in animals treated with different anti-proteinuric therapies. Methods. Nephrin gene expression and localization were examined in rats with streptozotocin-induced diabetes at 6 months duration (proteinuric phase) and at 7 days (pre-proteinuric phase). In addition, the effects of anti-proteinuric drug therapies were also assessed in long-term Diabetic rats, treated with either the angiotensin-converting enzyme inhibitor perindopril, or the blocker of advanced glycation end-product formation, aminoguanidine. Nephrin expression was determined using quantitative real-time PCR and in situ hybridization. Results. When compared with control animals, nephrin expression was reduced in the late proteinuric phase (45% reductionvs controls,P-0.01) but not in the early, pre-proteinuric phase of Experimental Diabetic Nephropathy. While ACE inhibition and aminoguanidine both reduced proteinuria, only the former attenuated the diabetes-associated reduction in nephrin expression. Conclusions. These findings suggests that reduction in nephrin may be a determinant of glomerular hyperpermeability in Diabetic Nephropathy. Attenuation of these changes with ACE inhibition suggest that this mechanism may contribute to the anti-proteinuric effects of this, but not all classes of drug which reduce urinary protein in Diabetic Nephropathy.
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expression of the slit diaphragm protein nephrin in Experimental Diabetic Nephropathy differing effects of anti proteinuric therapies
Nephrology Dialysis Transplantation, 2002Co-Authors: Darren J. Kelly, George Jerums, Sianna Panagiotopoulos, Alison J Cox, Petri Aaltonen, Jon R. Rumble, Robyn G Langham, Harry Holthöfer, Richard E. GilbertAbstract:Background. Mutations in the gene coding for the podocyte slit-pore membrane protein, nephrin, are responsible for the Finnish-type congenital nephrotic syndrome. The present study sought to examine whether nephrin expression may also be altered in Experimental diabetes, and how such changes related to the development of proteinuria. In addition, the study also sought to examine nephrin expression in animals treated with different anti-proteinuric therapies. Methods. Nephrin gene expression and localization were examined in rats with streptozotocin-induced diabetes at 6 months duration (proteinuric phase) and at 7 days (pre-proteinuric phase). In addition, the effects of anti-proteinuric drug therapies were also assessed in long-term Diabetic rats, treated with either the angiotensin-converting enzyme inhibitor perindopril, or the blocker of advanced glycation end-product formation, aminoguanidine. Nephrin expression was determined using quantitative real-time PCR and in situ hybridization. Results. When compared with control animals, nephrin expression was reduced in the late proteinuric phase (45% reductionvs controls,P-0.01) but not in the early, pre-proteinuric phase of Experimental Diabetic Nephropathy. While ACE inhibition and aminoguanidine both reduced proteinuria, only the former attenuated the diabetes-associated reduction in nephrin expression. Conclusions. These findings suggests that reduction in nephrin may be a determinant of glomerular hyperpermeability in Diabetic Nephropathy. Attenuation of these changes with ACE inhibition suggest that this mechanism may contribute to the anti-proteinuric effects of this, but not all classes of drug which reduce urinary protein in Diabetic Nephropathy.
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aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in Experimental Diabetic Nephropathy
Journal of The American Society of Nephrology, 2001Co-Authors: Darren J. Kelly, T Soulis, George Jerums, Richard E. Gilbert, Alison J Cox, Mark E. CooperAbstract:Profibrotic cytokines and the formation of advanced-glycation end products (AGE) have both been implicated in the pathogenesis of glomerulosclerosis in Diabetic kidney disease. However, tubulointerstitial pathology is also an important determinant of progressive renal dysfunction in Diabetic Nephropathy. This study sought to investigate the expression of profibrotic growth factors and matrix deposition in the glomerulus and the tubulointerstitium and to examine the effect of blocking AGE formation in Experimental Diabetic Nephropathy. Thirty-six male Sprague-Dawley rats were randomized into control and Diabetic groups. Diabetes was induced in 24 rats by streptozotocin. Twelve Diabetic rats were further randomized to receive the inhibitor of AGE formation, aminoguanidine (1 g/l drinking water). At 6 mo, Experimental diabetes was associated with a three-fold increase in expression of transforming growth factor (TGF)-beta1 (P < 0.01 versus control) and five-fold increase in platelet-derived growth factor (PDGF)-B gene expression (P < 0.01 versus control) in the tubulointerstitium. In situ hybridization demonstrated a diffuse increase in both TGF-beta1 and PDGF-B mRNA in renal tubules. Aminoguanidine attenuated not only the overexpression of TGF-beta1 and PDGF-B but also reduced type IV collagen deposition in Diabetic rats (P < 0.05). TGF-beta1 and PDGF mRNA within glomeruli were also similarly increased with diabetes and attenuated with aminoguanidine. The observed beneficial effects of aminoguanidine on the tubulointerstitium in Experimental diabetes suggest that AGE-mediated expression of profibrotic cytokines may contribute to tubulointerstitial injury and the pathogenesis of Diabetic Nephropathy.
Alison J Cox - One of the best experts on this subject based on the ideXlab platform.
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Expression of the slit‐diaphragm protein, nephrin, in Experimental Diabetic Nephropathy: differing effects of anti‐proteinuric therapies
Nephrology dialysis transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2002Co-Authors: Darren J. Kelly, George Jerums, Sianna Panagiotopoulos, Alison J Cox, Petri Aaltonen, Jon R. Rumble, Robyn G Langham, Harry Holthöfer, Richard E. GilbertAbstract:Background. Mutations in the gene coding for the podocyte slit-pore membrane protein, nephrin, are responsible for the Finnish-type congenital nephrotic syndrome. The present study sought to examine whether nephrin expression may also be altered in Experimental diabetes, and how such changes related to the development of proteinuria. In addition, the study also sought to examine nephrin expression in animals treated with different anti-proteinuric therapies. Methods. Nephrin gene expression and localization were examined in rats with streptozotocin-induced diabetes at 6 months duration (proteinuric phase) and at 7 days (pre-proteinuric phase). In addition, the effects of anti-proteinuric drug therapies were also assessed in long-term Diabetic rats, treated with either the angiotensin-converting enzyme inhibitor perindopril, or the blocker of advanced glycation end-product formation, aminoguanidine. Nephrin expression was determined using quantitative real-time PCR and in situ hybridization. Results. When compared with control animals, nephrin expression was reduced in the late proteinuric phase (45% reductionvs controls,P-0.01) but not in the early, pre-proteinuric phase of Experimental Diabetic Nephropathy. While ACE inhibition and aminoguanidine both reduced proteinuria, only the former attenuated the diabetes-associated reduction in nephrin expression. Conclusions. These findings suggests that reduction in nephrin may be a determinant of glomerular hyperpermeability in Diabetic Nephropathy. Attenuation of these changes with ACE inhibition suggest that this mechanism may contribute to the anti-proteinuric effects of this, but not all classes of drug which reduce urinary protein in Diabetic Nephropathy.
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expression of the slit diaphragm protein nephrin in Experimental Diabetic Nephropathy differing effects of anti proteinuric therapies
Nephrology Dialysis Transplantation, 2002Co-Authors: Darren J. Kelly, George Jerums, Sianna Panagiotopoulos, Alison J Cox, Petri Aaltonen, Jon R. Rumble, Robyn G Langham, Harry Holthöfer, Richard E. GilbertAbstract:Background. Mutations in the gene coding for the podocyte slit-pore membrane protein, nephrin, are responsible for the Finnish-type congenital nephrotic syndrome. The present study sought to examine whether nephrin expression may also be altered in Experimental diabetes, and how such changes related to the development of proteinuria. In addition, the study also sought to examine nephrin expression in animals treated with different anti-proteinuric therapies. Methods. Nephrin gene expression and localization were examined in rats with streptozotocin-induced diabetes at 6 months duration (proteinuric phase) and at 7 days (pre-proteinuric phase). In addition, the effects of anti-proteinuric drug therapies were also assessed in long-term Diabetic rats, treated with either the angiotensin-converting enzyme inhibitor perindopril, or the blocker of advanced glycation end-product formation, aminoguanidine. Nephrin expression was determined using quantitative real-time PCR and in situ hybridization. Results. When compared with control animals, nephrin expression was reduced in the late proteinuric phase (45% reductionvs controls,P-0.01) but not in the early, pre-proteinuric phase of Experimental Diabetic Nephropathy. While ACE inhibition and aminoguanidine both reduced proteinuria, only the former attenuated the diabetes-associated reduction in nephrin expression. Conclusions. These findings suggests that reduction in nephrin may be a determinant of glomerular hyperpermeability in Diabetic Nephropathy. Attenuation of these changes with ACE inhibition suggest that this mechanism may contribute to the anti-proteinuric effects of this, but not all classes of drug which reduce urinary protein in Diabetic Nephropathy.
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aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in Experimental Diabetic Nephropathy
Journal of The American Society of Nephrology, 2001Co-Authors: Darren J. Kelly, T Soulis, George Jerums, Richard E. Gilbert, Alison J Cox, Mark E. CooperAbstract:Profibrotic cytokines and the formation of advanced-glycation end products (AGE) have both been implicated in the pathogenesis of glomerulosclerosis in Diabetic kidney disease. However, tubulointerstitial pathology is also an important determinant of progressive renal dysfunction in Diabetic Nephropathy. This study sought to investigate the expression of profibrotic growth factors and matrix deposition in the glomerulus and the tubulointerstitium and to examine the effect of blocking AGE formation in Experimental Diabetic Nephropathy. Thirty-six male Sprague-Dawley rats were randomized into control and Diabetic groups. Diabetes was induced in 24 rats by streptozotocin. Twelve Diabetic rats were further randomized to receive the inhibitor of AGE formation, aminoguanidine (1 g/l drinking water). At 6 mo, Experimental diabetes was associated with a three-fold increase in expression of transforming growth factor (TGF)-beta1 (P < 0.01 versus control) and five-fold increase in platelet-derived growth factor (PDGF)-B gene expression (P < 0.01 versus control) in the tubulointerstitium. In situ hybridization demonstrated a diffuse increase in both TGF-beta1 and PDGF-B mRNA in renal tubules. Aminoguanidine attenuated not only the overexpression of TGF-beta1 and PDGF-B but also reduced type IV collagen deposition in Diabetic rats (P < 0.05). TGF-beta1 and PDGF mRNA within glomeruli were also similarly increased with diabetes and attenuated with aminoguanidine. The observed beneficial effects of aminoguanidine on the tubulointerstitium in Experimental diabetes suggest that AGE-mediated expression of profibrotic cytokines may contribute to tubulointerstitial injury and the pathogenesis of Diabetic Nephropathy.
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Aminoguanidine Ameliorates Overexpression of Prosclerotic Growth Factors and Collagen Deposition in Experimental Diabetic Nephropathy
Journal of the American Society of Nephrology, 2001Co-Authors: Darren J. Kelly, T Soulis, George Jerums, Richard E. Gilbert, Alison J Cox, Mark E. CooperAbstract:Abstract. Profibrotic cytokines and the formation of advanced-glycation end products (AGE) have both been implicated in the pathogenesis of glomerulosclerosis in Diabetic kidney disease. However, tubulointerstitial pathology is also an important determinant of progressive renal dysfunction in Diabetic Nephropathy. This study sought to investigate the expression of profibrotic growth factors and matrix deposition in the glomerulus and the tubulointerstitium and to examine the effect of blocking AGE formation in Experimental Diabetic Nephropathy. Thirty-six male Sprague-Dawley rats were randomized into control and Diabetic groups. Diabetes was induced in 24 rats by streptozotocin. Twelve Diabetic rats were further randomized to receive the inhibitor of AGE formation, aminoguanidine (1 g/l drinking water). At 6 mo, Experimental diabetes was associated with a three-fold increase in expression of transforming growth factor (TGF)-β1 (P < 0.01 versus control) and five-fold increase in platelet-derived growth factor (PDGF)-B gene expression (P < 0.01 versus control) in the tubulointerstitium. In situ hybridization demonstrated a diffuse increase in both TGF-β1 and PDGF-B mRNA in renal tubules. Aminoguanidine attenuated not only the overexpression of TGF-β1 and PDGF-B but also reduced type IV collagen deposition in Diabetic rats (P < 0.05). TGF-β1 and PDGF mRNA within glomeruli were also similarly increased with diabetes and attenuated with aminoguanidine. The observed beneficial effects of aminoguanidine on the tubulointerstitium in Experimental diabetes suggest that AGE-mediated expression of profibrotic cytokines may contribute to tubulointerstitial injury and the pathogenesis of Diabetic Nephropathy.
