Cellular mechanisms in the development and progression of diabetic nephropathy: activation of the DAG-PKC-ERK pathway.
Diabetic nephropathy is characterized functionally by glomerular hyperfiltration and albuminuria and histologically by the expansion of glomerular mesangium. We and others have found that protein kinase C (PKC) is activated through an increase in de novo synthesis of diacylglycerol (DAG) from glucose in glomerular mesangial cells cultured under high glucose conditions and in glomeruli of diabetic rats. The activation of PKC could activate further various intracellular signal transduction systems, such as extracellular regulated kinase (ERK). The activation of the DAG-PKC-ERK pathway is considered to be one of the important molecular mechanisms of the development and progression of diabetic nephropathy. To prove this hypothesis, we examined whether the inhibition of the DAG-PKC-ERK pathway could prevent the development of glomerular dysfunction in diabetic animals. First, we found that thiazolidinedione compounds could inhibit PKC activation by activating DAG kinase. Thiazolidinedione compounds were able to prevent glomerular hyperfiltration, albuminuria, and excessive production of extracellular matrix proteins in glomeruli in streptozotocin-induced diabetic rats, a model for type 1 diabetes. Second, we tried to inhibit PKC directly by oral administration of PKC beta inhibitor. PKC beta inhibitor could prevent albuminuria and mesangial expansion in db/db mice, a model for type 2 diabetes. These results confirmed the importance of the activation of the DAG-PKC-ERK pathway in the development of glomerular dysfunction in diabetes.
Haneda
M
M
Third Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan. haneda@belle.shiga-med.ac.jp
Koya
D
D
Kikkawa
R
R
D000818:Animals; D002839:Chromans / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000517:prevention & control; D019852:Diacylglycerol Kinase / Q000187:drug effects*; D018450:Disease Progression; D004789:Enzyme Activation; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000077205:Pioglitazone; D010940:Plant Proteins / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D064546:Protein Kinase C beta; D051381:Rats; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D000077288:Troglitazone
D002839:Chromans; C102164:DAG protein, Antirrhinum majus; D007527:Isoenzymes; D010940:Plant Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D020928:Mitogen-Activated Protein Kinases; D000077288:Troglitazone; D000077205:Pioglitazone