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The glomerular mesangium in diabetes mellitus
1Department of Pathology, University of Texas Health Science Center, San Antonio.
Abstract:
Like the renal glomerular mesangium in patients with diabetic nephropathy, glomerular mesangial cell cultures grown in 30 mM glucose accumulate increased amounts of the extracellular matrix (ECM) proteins fibronectin, laminin, and type IV collagen. This is due to increased ECM protein synthesis and mRNA levels. Similar to other cells types that are affected by the diabetic state (such as, vascular cells and peripheral nerve), mesangial cells transport glucose by an insulin-independent, facilitated diffusion transport system. Kinetic studies reveal that intracellular glucose levels may reach the ambient glucose concentrations achieved in diabetes. Growth studies reveal that glucose does not exert its effect on mesangial cell ECM accumulation by affecting cell growth, but rather it causes an increase in diacylglycerol (DAG) mass and activates protein kinase C. Agents such as phorbol myristate acetate (PMA) and the cell permeable DAG analogue, oleoyl acetyl glycerol (OAG) which activate protein kinase C also increase ECM mRNAs. These results implicate protein kinase C activation in the increased ECM accumulation observed in mesangial cell cultures grown in high glucose.
Insights
High glucose levels in diabetic nephropathy increase extracellular matrix (ECM) proteins in mesangial cells. This occurs via protein kinase C activation, not by affecting cell growth.
Area of Science:
- Nephrology
- Diabetology
- Cell Biology
Background:
- Diabetic nephropathy is characterized by extracellular matrix (ECM) accumulation in the renal glomerulus.
- Glomerular mesangial cells play a crucial role in kidney function and are affected by high glucose levels in diabetes.
Purpose of the Study:
- To investigate the mechanism by which high glucose induces ECM accumulation in glomerular mesangial cells.
- To determine the role of protein kinase C (PKC) activation in this process.
Main Methods:
- Cultured human glomerular mesangial cells were exposed to high glucose concentrations (30 mM).
- Levels of ECM proteins (fibronectin, laminin, type IV collagen) and their corresponding mRNA were measured.
- Intracellular signaling pathways, including diacylglycerol (DAG) mass and PKC activity, were assessed.
- The effects of PKC activators (phorbol myristate acetate, oleoyl acetyl glycerol) on ECM production were examined.
Main Results:
- High glucose significantly increased the accumulation of ECM proteins and their mRNA levels in mesangial cells.
- Intracellular glucose levels in mesangial cells reached concentrations comparable to those in diabetic patients.
- High glucose led to increased diacylglycerol (DAG) mass and activated protein kinase C (PKC).
- PKC activators mimicked the effect of high glucose, increasing ECM mRNA levels.
Conclusions:
- High glucose-induced ECM accumulation in mesangial cells is mediated by the activation of protein kinase C (PKC).
- This pathway is independent of effects on cell growth.
- Understanding this mechanism may offer therapeutic targets for diabetic nephropathy.