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Daisuke Koya - One of the best experts on this subject based on the ideXlab platform.
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thiazolidinedione compounds ameliorate Glomerular Dysfunction independent of their insulin sensitizing action in diabetic rats
Diabetes, 2000Co-Authors: Keiji Isshiki, Masakazu Haneda, Daisuke Koya, Shiro Maeda, Toshiro Sugimoto, Ryuichi KikkawaAbstract:Thiazolidinedione (TZD) compounds are widely used as oral hypoglycemic agents. Herein, we provide evidence showing that troglitazone, one of the TZD compounds, is able to prevent Glomerular Dysfunction in diabetic rats through a novel mechanism independent of its insulin-sensitizing action. We examined the effect of troglitazone on functional and biochemical parameters of glomeruli in streptozotocin-induced diabetic rats. Troglitazone was able to prevent not only diabetic Glomerular hyperfiltration and albuminuria, but an increase in mRNA expression of extracellular matrix proteins and transforming growth factor-beta1 in glomeruli of diabetic rats, without changing blood glucose levels. Biochemically, an increase in diacylglycerol (DAG) contents and the activation of the protein kinase C (PKC)-extracellular signal-regulated kinase (ERK) pathway in glomeruli of diabetic rats were abrogated by troglitazone. The activation of DAG-PKC-ERK pathways in vitro in mesangial cells cultured under high glucose conditions was also inhibited by troglitazone. Troglitazone enhanced the activities of DAG kinase, which could metabolize DAG to phosphatidic acid, in both glomeruli of diabetic rats and mesangial cells cultured under high glucose conditions. Surprisingly, pioglitazone, another TZD compound without alpha-tocopherol moiety in its structure, also prevented the activation of the DAG-PKC pathway and activated DAG kinase in mesangial cells cultured under high glucose conditions. These results may identify the TZDs as possible new therapeutic agents for diabetic nephropathy that prevent Glomerular Dysfunction through the inhibition of the DAG-PKC-ERK pathway.
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amelioration of accelerated diabetic mesangial expansion by treatment with a pkc β inhibitor in diabetic db db mice a rodent model for type 2 diabetes
The FASEB Journal, 2000Co-Authors: Daisuke Koya, Keiji Isshiki, Masakazu Haneda, Shiro Maeda, Toshiro Sugimoto, Hiroko Nakagawa, Haruhisa Sato, Hitoshi Yasuda, Atsunori Kashiwagi, Kirk D WaysAbstract:Activation of protein kinase C (PKC) is implicated as an important mechanism by which diabetes causes vascular complications. We have recently shown that a PKC β inhibitor ameliorates not only early diabetes-induced Glomerular Dysfunction such as Glomerular hyperfiltration and albuminuria, but also overexpression of Glomerular mRNA for transforming growth factor β1 (TGF-β1) and extracellular matrix (ECM) proteins in streptozotocin-induced diabetic rats, a model for type 1 diabetes. In this study, we examined the long-term effects of a PKC β inhibitor on Glomerular histology as well as on biochemical and functional abnormalities in glomeruli of db/db mice, a model for type 2 diabetes. Administration of a PKC β inhibitor reduced urinary albumin excretion rates and inhibited Glomerular PKC activation in diabetic db/db mice. Administration of a PKC β inhibitor also prevented the mesangial expansion observed in diabetic db/db mice, possibly through attenuation of Glomerular expression of TGF-β and ECM proteins...
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amelioration of accelerated diabetic mesangial expansion by treatment with a pkc β inhibitor in diabetic db db mice a rodent model for type 2 diabetes
The FASEB Journal, 2000Co-Authors: Daisuke Koya, Keiji Isshiki, Masakazu Haneda, Shiro Maeda, Toshiro Sugimoto, Hiroko Nakagawa, Haruhisa Sato, Hitoshi Yasuda, Atsunori Kashiwagi, Kirk D WaysAbstract:Activation of protein kinase C (PKC) is implicated as an important mechanism by which diabetes causes vascular complications. We have recently shown that a PKC beta inhibitor ameliorates not only early diabetes-induced Glomerular Dysfunction such as Glomerular hyperfiltration and albuminuria, but also overexpression of Glomerular mRNA for transforming growth factor beta1 (TGF-beta1) and extracellular matrix (ECM) proteins in streptozotocin-induced diabetic rats, a model for type 1 diabetes. In this study, we examined the long-term effects of a PKC beta inhibitor on Glomerular histology as well as on biochemical and functional abnormalities in glomeruli of db/db mice, a model for type 2 diabetes. Administration of a PKC beta inhibitor reduced urinary albumin excretion rates and inhibited Glomerular PKC activation in diabetic db/db mice. Administration of a PKC beta inhibitor also prevented the mesangial expansion observed in diabetic db/db mice, possibly through attenuation of Glomerular expression of TGF-beta and ECM proteins such as fibronectin and type IV collagen. These findings provide the first in vivo evidence that the long-term inhibition of PKC activation in the renal glomeruli can ameliorate Glomerular pathologies in diabetic state, and thus suggest that a PKC beta inhibitor might be an useful therapeutic strategy for the treatment of diabetic nephropathy.
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prevention of Glomerular Dysfunction in diabetic rats by treatment with d alpha tocopherol
Journal of The American Society of Nephrology, 1997Co-Authors: Daisuke Koya, Inkyu Lee, H Ishii, Hideo Kanoh, George L KingAbstract:Because d-alpha-tocopherol (vitamin E) has been shown to decrease diacylglycerol (DAG) levels and prevent the activation of protein kinase C (PKC), which is associated with retinal and renal Dysfunctions in diabetes, the study presented here characterized the effect of d-alpha-tocopherol treatment to prevent Glomerular hyperfiltration and increased albuminuria as well as PKC activities in streptozotocin (STZ)-induced diabetic rats. Two weeks after the induction of diabetes, total DAG content and PKC activity in glomeruli were significantly increased in diabetic rats by 106.4 +/- 16.8% and 66.4 +/- 8.4%, respectively, compared with control rats. Intraperitoneal injection of d-alpha-tocopherol (40 mg/kg of body weight) every other day prevented the increases in total DAG content and PKC activity in glomeruli of diabetic rats. Glomerular filtration rate (GFR) and filtration fraction (FF) were significantly elevated to 4.98 +/- 0.34 mL/min and 0.36 +/- 0.05, respectively, in diabetic rats, compared with 2.90 +/- 0.14 mL/min and 0.25 +/- 0.02, respectively, in control rats. These hemodynamic abnormalities in diabetic rats were normalized to 2.98 +/- 0.09 mL/min and 0.24 +/- 0.01, respectively, by d-alpha-tocopherol. Albuminuria in 10-wk diabetic rats was significantly increased to 9.1 +/- 2.2 mg/day compared with 1.2 +/- 0.3 mg/day in control rats, whereas d-alpha-tocopherol treatment improved albumin excretion rate to 2.4 +/- 0.6 mg/day in diabetic rats. To clarify the mechanism of d-alpha-tocopherol9s effect on DAG-PKC pathway, the activity and protein levels of DAG kinase alpha and gamma, which metabolize DAG to phosphatidic acid, were examined. Treatment with d-alpha-tocopherol increased DAG kinase activity in the glomeruli of both control and diabetic rats, by 22.6 +/- 3.6% and 28.5 +/- 2.3% respectively, although no differences were observed in the basal DAG kinase activity between control and diabetic rats. Because immunoblotting studies did not exhibit any difference in the protein levels of DAG kinase alpha and gamma, the effect of d-alpha-tocopherol is probably modulating the enzyme kinetics of DAG kinase. These findings suggest that the increases in DAG-PKC pathway play an important role for the development of Glomerular hyperfiltration and increased albuminuria in diabetes and that d-alpha-tocopherol treatment could be preventing early changes of diabetic renal Dysfunctions by normalizing the increases in DAG and PKC levels in Glomerular cells.
Kirk D Ways - One of the best experts on this subject based on the ideXlab platform.
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amelioration of accelerated diabetic mesangial expansion by treatment with a pkc β inhibitor in diabetic db db mice a rodent model for type 2 diabetes
The FASEB Journal, 2000Co-Authors: Daisuke Koya, Keiji Isshiki, Masakazu Haneda, Shiro Maeda, Toshiro Sugimoto, Hiroko Nakagawa, Haruhisa Sato, Hitoshi Yasuda, Atsunori Kashiwagi, Kirk D WaysAbstract:Activation of protein kinase C (PKC) is implicated as an important mechanism by which diabetes causes vascular complications. We have recently shown that a PKC β inhibitor ameliorates not only early diabetes-induced Glomerular Dysfunction such as Glomerular hyperfiltration and albuminuria, but also overexpression of Glomerular mRNA for transforming growth factor β1 (TGF-β1) and extracellular matrix (ECM) proteins in streptozotocin-induced diabetic rats, a model for type 1 diabetes. In this study, we examined the long-term effects of a PKC β inhibitor on Glomerular histology as well as on biochemical and functional abnormalities in glomeruli of db/db mice, a model for type 2 diabetes. Administration of a PKC β inhibitor reduced urinary albumin excretion rates and inhibited Glomerular PKC activation in diabetic db/db mice. Administration of a PKC β inhibitor also prevented the mesangial expansion observed in diabetic db/db mice, possibly through attenuation of Glomerular expression of TGF-β and ECM proteins...
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amelioration of accelerated diabetic mesangial expansion by treatment with a pkc β inhibitor in diabetic db db mice a rodent model for type 2 diabetes
The FASEB Journal, 2000Co-Authors: Daisuke Koya, Keiji Isshiki, Masakazu Haneda, Shiro Maeda, Toshiro Sugimoto, Hiroko Nakagawa, Haruhisa Sato, Hitoshi Yasuda, Atsunori Kashiwagi, Kirk D WaysAbstract:Activation of protein kinase C (PKC) is implicated as an important mechanism by which diabetes causes vascular complications. We have recently shown that a PKC beta inhibitor ameliorates not only early diabetes-induced Glomerular Dysfunction such as Glomerular hyperfiltration and albuminuria, but also overexpression of Glomerular mRNA for transforming growth factor beta1 (TGF-beta1) and extracellular matrix (ECM) proteins in streptozotocin-induced diabetic rats, a model for type 1 diabetes. In this study, we examined the long-term effects of a PKC beta inhibitor on Glomerular histology as well as on biochemical and functional abnormalities in glomeruli of db/db mice, a model for type 2 diabetes. Administration of a PKC beta inhibitor reduced urinary albumin excretion rates and inhibited Glomerular PKC activation in diabetic db/db mice. Administration of a PKC beta inhibitor also prevented the mesangial expansion observed in diabetic db/db mice, possibly through attenuation of Glomerular expression of TGF-beta and ECM proteins such as fibronectin and type IV collagen. These findings provide the first in vivo evidence that the long-term inhibition of PKC activation in the renal glomeruli can ameliorate Glomerular pathologies in diabetic state, and thus suggest that a PKC beta inhibitor might be an useful therapeutic strategy for the treatment of diabetic nephropathy.
Keiji Isshiki - One of the best experts on this subject based on the ideXlab platform.
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thiazolidinedione compounds ameliorate Glomerular Dysfunction independent of their insulin sensitizing action in diabetic rats
Diabetes, 2000Co-Authors: Keiji Isshiki, Masakazu Haneda, Daisuke Koya, Shiro Maeda, Toshiro Sugimoto, Ryuichi KikkawaAbstract:Thiazolidinedione (TZD) compounds are widely used as oral hypoglycemic agents. Herein, we provide evidence showing that troglitazone, one of the TZD compounds, is able to prevent Glomerular Dysfunction in diabetic rats through a novel mechanism independent of its insulin-sensitizing action. We examined the effect of troglitazone on functional and biochemical parameters of glomeruli in streptozotocin-induced diabetic rats. Troglitazone was able to prevent not only diabetic Glomerular hyperfiltration and albuminuria, but an increase in mRNA expression of extracellular matrix proteins and transforming growth factor-beta1 in glomeruli of diabetic rats, without changing blood glucose levels. Biochemically, an increase in diacylglycerol (DAG) contents and the activation of the protein kinase C (PKC)-extracellular signal-regulated kinase (ERK) pathway in glomeruli of diabetic rats were abrogated by troglitazone. The activation of DAG-PKC-ERK pathways in vitro in mesangial cells cultured under high glucose conditions was also inhibited by troglitazone. Troglitazone enhanced the activities of DAG kinase, which could metabolize DAG to phosphatidic acid, in both glomeruli of diabetic rats and mesangial cells cultured under high glucose conditions. Surprisingly, pioglitazone, another TZD compound without alpha-tocopherol moiety in its structure, also prevented the activation of the DAG-PKC pathway and activated DAG kinase in mesangial cells cultured under high glucose conditions. These results may identify the TZDs as possible new therapeutic agents for diabetic nephropathy that prevent Glomerular Dysfunction through the inhibition of the DAG-PKC-ERK pathway.
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amelioration of accelerated diabetic mesangial expansion by treatment with a pkc β inhibitor in diabetic db db mice a rodent model for type 2 diabetes
The FASEB Journal, 2000Co-Authors: Daisuke Koya, Keiji Isshiki, Masakazu Haneda, Shiro Maeda, Toshiro Sugimoto, Hiroko Nakagawa, Haruhisa Sato, Hitoshi Yasuda, Atsunori Kashiwagi, Kirk D WaysAbstract:Activation of protein kinase C (PKC) is implicated as an important mechanism by which diabetes causes vascular complications. We have recently shown that a PKC β inhibitor ameliorates not only early diabetes-induced Glomerular Dysfunction such as Glomerular hyperfiltration and albuminuria, but also overexpression of Glomerular mRNA for transforming growth factor β1 (TGF-β1) and extracellular matrix (ECM) proteins in streptozotocin-induced diabetic rats, a model for type 1 diabetes. In this study, we examined the long-term effects of a PKC β inhibitor on Glomerular histology as well as on biochemical and functional abnormalities in glomeruli of db/db mice, a model for type 2 diabetes. Administration of a PKC β inhibitor reduced urinary albumin excretion rates and inhibited Glomerular PKC activation in diabetic db/db mice. Administration of a PKC β inhibitor also prevented the mesangial expansion observed in diabetic db/db mice, possibly through attenuation of Glomerular expression of TGF-β and ECM proteins...
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amelioration of accelerated diabetic mesangial expansion by treatment with a pkc β inhibitor in diabetic db db mice a rodent model for type 2 diabetes
The FASEB Journal, 2000Co-Authors: Daisuke Koya, Keiji Isshiki, Masakazu Haneda, Shiro Maeda, Toshiro Sugimoto, Hiroko Nakagawa, Haruhisa Sato, Hitoshi Yasuda, Atsunori Kashiwagi, Kirk D WaysAbstract:Activation of protein kinase C (PKC) is implicated as an important mechanism by which diabetes causes vascular complications. We have recently shown that a PKC beta inhibitor ameliorates not only early diabetes-induced Glomerular Dysfunction such as Glomerular hyperfiltration and albuminuria, but also overexpression of Glomerular mRNA for transforming growth factor beta1 (TGF-beta1) and extracellular matrix (ECM) proteins in streptozotocin-induced diabetic rats, a model for type 1 diabetes. In this study, we examined the long-term effects of a PKC beta inhibitor on Glomerular histology as well as on biochemical and functional abnormalities in glomeruli of db/db mice, a model for type 2 diabetes. Administration of a PKC beta inhibitor reduced urinary albumin excretion rates and inhibited Glomerular PKC activation in diabetic db/db mice. Administration of a PKC beta inhibitor also prevented the mesangial expansion observed in diabetic db/db mice, possibly through attenuation of Glomerular expression of TGF-beta and ECM proteins such as fibronectin and type IV collagen. These findings provide the first in vivo evidence that the long-term inhibition of PKC activation in the renal glomeruli can ameliorate Glomerular pathologies in diabetic state, and thus suggest that a PKC beta inhibitor might be an useful therapeutic strategy for the treatment of diabetic nephropathy.
Shiro Maeda - One of the best experts on this subject based on the ideXlab platform.
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thiazolidinedione compounds ameliorate Glomerular Dysfunction independent of their insulin sensitizing action in diabetic rats
Diabetes, 2000Co-Authors: Keiji Isshiki, Masakazu Haneda, Daisuke Koya, Shiro Maeda, Toshiro Sugimoto, Ryuichi KikkawaAbstract:Thiazolidinedione (TZD) compounds are widely used as oral hypoglycemic agents. Herein, we provide evidence showing that troglitazone, one of the TZD compounds, is able to prevent Glomerular Dysfunction in diabetic rats through a novel mechanism independent of its insulin-sensitizing action. We examined the effect of troglitazone on functional and biochemical parameters of glomeruli in streptozotocin-induced diabetic rats. Troglitazone was able to prevent not only diabetic Glomerular hyperfiltration and albuminuria, but an increase in mRNA expression of extracellular matrix proteins and transforming growth factor-beta1 in glomeruli of diabetic rats, without changing blood glucose levels. Biochemically, an increase in diacylglycerol (DAG) contents and the activation of the protein kinase C (PKC)-extracellular signal-regulated kinase (ERK) pathway in glomeruli of diabetic rats were abrogated by troglitazone. The activation of DAG-PKC-ERK pathways in vitro in mesangial cells cultured under high glucose conditions was also inhibited by troglitazone. Troglitazone enhanced the activities of DAG kinase, which could metabolize DAG to phosphatidic acid, in both glomeruli of diabetic rats and mesangial cells cultured under high glucose conditions. Surprisingly, pioglitazone, another TZD compound without alpha-tocopherol moiety in its structure, also prevented the activation of the DAG-PKC pathway and activated DAG kinase in mesangial cells cultured under high glucose conditions. These results may identify the TZDs as possible new therapeutic agents for diabetic nephropathy that prevent Glomerular Dysfunction through the inhibition of the DAG-PKC-ERK pathway.
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amelioration of accelerated diabetic mesangial expansion by treatment with a pkc β inhibitor in diabetic db db mice a rodent model for type 2 diabetes
The FASEB Journal, 2000Co-Authors: Daisuke Koya, Keiji Isshiki, Masakazu Haneda, Shiro Maeda, Toshiro Sugimoto, Hiroko Nakagawa, Haruhisa Sato, Hitoshi Yasuda, Atsunori Kashiwagi, Kirk D WaysAbstract:Activation of protein kinase C (PKC) is implicated as an important mechanism by which diabetes causes vascular complications. We have recently shown that a PKC β inhibitor ameliorates not only early diabetes-induced Glomerular Dysfunction such as Glomerular hyperfiltration and albuminuria, but also overexpression of Glomerular mRNA for transforming growth factor β1 (TGF-β1) and extracellular matrix (ECM) proteins in streptozotocin-induced diabetic rats, a model for type 1 diabetes. In this study, we examined the long-term effects of a PKC β inhibitor on Glomerular histology as well as on biochemical and functional abnormalities in glomeruli of db/db mice, a model for type 2 diabetes. Administration of a PKC β inhibitor reduced urinary albumin excretion rates and inhibited Glomerular PKC activation in diabetic db/db mice. Administration of a PKC β inhibitor also prevented the mesangial expansion observed in diabetic db/db mice, possibly through attenuation of Glomerular expression of TGF-β and ECM proteins...
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amelioration of accelerated diabetic mesangial expansion by treatment with a pkc β inhibitor in diabetic db db mice a rodent model for type 2 diabetes
The FASEB Journal, 2000Co-Authors: Daisuke Koya, Keiji Isshiki, Masakazu Haneda, Shiro Maeda, Toshiro Sugimoto, Hiroko Nakagawa, Haruhisa Sato, Hitoshi Yasuda, Atsunori Kashiwagi, Kirk D WaysAbstract:Activation of protein kinase C (PKC) is implicated as an important mechanism by which diabetes causes vascular complications. We have recently shown that a PKC beta inhibitor ameliorates not only early diabetes-induced Glomerular Dysfunction such as Glomerular hyperfiltration and albuminuria, but also overexpression of Glomerular mRNA for transforming growth factor beta1 (TGF-beta1) and extracellular matrix (ECM) proteins in streptozotocin-induced diabetic rats, a model for type 1 diabetes. In this study, we examined the long-term effects of a PKC beta inhibitor on Glomerular histology as well as on biochemical and functional abnormalities in glomeruli of db/db mice, a model for type 2 diabetes. Administration of a PKC beta inhibitor reduced urinary albumin excretion rates and inhibited Glomerular PKC activation in diabetic db/db mice. Administration of a PKC beta inhibitor also prevented the mesangial expansion observed in diabetic db/db mice, possibly through attenuation of Glomerular expression of TGF-beta and ECM proteins such as fibronectin and type IV collagen. These findings provide the first in vivo evidence that the long-term inhibition of PKC activation in the renal glomeruli can ameliorate Glomerular pathologies in diabetic state, and thus suggest that a PKC beta inhibitor might be an useful therapeutic strategy for the treatment of diabetic nephropathy.
Toshiro Sugimoto - One of the best experts on this subject based on the ideXlab platform.
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thiazolidinedione compounds ameliorate Glomerular Dysfunction independent of their insulin sensitizing action in diabetic rats
Diabetes, 2000Co-Authors: Keiji Isshiki, Masakazu Haneda, Daisuke Koya, Shiro Maeda, Toshiro Sugimoto, Ryuichi KikkawaAbstract:Thiazolidinedione (TZD) compounds are widely used as oral hypoglycemic agents. Herein, we provide evidence showing that troglitazone, one of the TZD compounds, is able to prevent Glomerular Dysfunction in diabetic rats through a novel mechanism independent of its insulin-sensitizing action. We examined the effect of troglitazone on functional and biochemical parameters of glomeruli in streptozotocin-induced diabetic rats. Troglitazone was able to prevent not only diabetic Glomerular hyperfiltration and albuminuria, but an increase in mRNA expression of extracellular matrix proteins and transforming growth factor-beta1 in glomeruli of diabetic rats, without changing blood glucose levels. Biochemically, an increase in diacylglycerol (DAG) contents and the activation of the protein kinase C (PKC)-extracellular signal-regulated kinase (ERK) pathway in glomeruli of diabetic rats were abrogated by troglitazone. The activation of DAG-PKC-ERK pathways in vitro in mesangial cells cultured under high glucose conditions was also inhibited by troglitazone. Troglitazone enhanced the activities of DAG kinase, which could metabolize DAG to phosphatidic acid, in both glomeruli of diabetic rats and mesangial cells cultured under high glucose conditions. Surprisingly, pioglitazone, another TZD compound without alpha-tocopherol moiety in its structure, also prevented the activation of the DAG-PKC pathway and activated DAG kinase in mesangial cells cultured under high glucose conditions. These results may identify the TZDs as possible new therapeutic agents for diabetic nephropathy that prevent Glomerular Dysfunction through the inhibition of the DAG-PKC-ERK pathway.
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amelioration of accelerated diabetic mesangial expansion by treatment with a pkc β inhibitor in diabetic db db mice a rodent model for type 2 diabetes
The FASEB Journal, 2000Co-Authors: Daisuke Koya, Keiji Isshiki, Masakazu Haneda, Shiro Maeda, Toshiro Sugimoto, Hiroko Nakagawa, Haruhisa Sato, Hitoshi Yasuda, Atsunori Kashiwagi, Kirk D WaysAbstract:Activation of protein kinase C (PKC) is implicated as an important mechanism by which diabetes causes vascular complications. We have recently shown that a PKC β inhibitor ameliorates not only early diabetes-induced Glomerular Dysfunction such as Glomerular hyperfiltration and albuminuria, but also overexpression of Glomerular mRNA for transforming growth factor β1 (TGF-β1) and extracellular matrix (ECM) proteins in streptozotocin-induced diabetic rats, a model for type 1 diabetes. In this study, we examined the long-term effects of a PKC β inhibitor on Glomerular histology as well as on biochemical and functional abnormalities in glomeruli of db/db mice, a model for type 2 diabetes. Administration of a PKC β inhibitor reduced urinary albumin excretion rates and inhibited Glomerular PKC activation in diabetic db/db mice. Administration of a PKC β inhibitor also prevented the mesangial expansion observed in diabetic db/db mice, possibly through attenuation of Glomerular expression of TGF-β and ECM proteins...
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amelioration of accelerated diabetic mesangial expansion by treatment with a pkc β inhibitor in diabetic db db mice a rodent model for type 2 diabetes
The FASEB Journal, 2000Co-Authors: Daisuke Koya, Keiji Isshiki, Masakazu Haneda, Shiro Maeda, Toshiro Sugimoto, Hiroko Nakagawa, Haruhisa Sato, Hitoshi Yasuda, Atsunori Kashiwagi, Kirk D WaysAbstract:Activation of protein kinase C (PKC) is implicated as an important mechanism by which diabetes causes vascular complications. We have recently shown that a PKC beta inhibitor ameliorates not only early diabetes-induced Glomerular Dysfunction such as Glomerular hyperfiltration and albuminuria, but also overexpression of Glomerular mRNA for transforming growth factor beta1 (TGF-beta1) and extracellular matrix (ECM) proteins in streptozotocin-induced diabetic rats, a model for type 1 diabetes. In this study, we examined the long-term effects of a PKC beta inhibitor on Glomerular histology as well as on biochemical and functional abnormalities in glomeruli of db/db mice, a model for type 2 diabetes. Administration of a PKC beta inhibitor reduced urinary albumin excretion rates and inhibited Glomerular PKC activation in diabetic db/db mice. Administration of a PKC beta inhibitor also prevented the mesangial expansion observed in diabetic db/db mice, possibly through attenuation of Glomerular expression of TGF-beta and ECM proteins such as fibronectin and type IV collagen. These findings provide the first in vivo evidence that the long-term inhibition of PKC activation in the renal glomeruli can ameliorate Glomerular pathologies in diabetic state, and thus suggest that a PKC beta inhibitor might be an useful therapeutic strategy for the treatment of diabetic nephropathy.