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Lipoprotein (a) stimulates mitogen activated protein kinase in human mesangial cells
U F Mondorf1, A Piiper, M Herrero
1Division of Nephrology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. mondorf@em.uni-frankfurt.de
Abstract:
Evidence suggests an important role of elevated serum lipoproteins in the progression of renal glomerulosclerosis. We report here that lipoprotein (a) (Lp(a)) increased phosphorylation and activity of mitogen activated protein kinase (MAPK) in human mesangial cells. When protein kinase C (PKC) was depleted by long-term incubation with the phorbol 12-O-myristate 13-acetate the effect of Lp(a) on MAPK activation was completely inhibited. Forskolin, a stimulator of the adenylyl cyclase, and dibutyryl-cAMP reduced the effect of Lp(a) on MAPK phosphorylation and activation. We conclude that Lp(a) stimulates the MAPK cascade via activation of PKC and that activation of protein kinase A counteracts Lp(a) induced MAPK activation in human mesangial cells.
Insights
Elevated lipoprotein (a) activates mitogen-activated protein kinase (MAPK) in kidney cells via protein kinase C (PKC). Protein kinase A activation counteracts this effect, suggesting a role in glomerulosclerosis.
Area of Science:
- Nephrology
- Cell Biology
- Biochemistry
Background:
- Elevated serum lipoproteins are implicated in the progression of renal glomerulosclerosis.
- Lipoprotein (a) (Lp(a)) is a specific type of lipoprotein linked to cardiovascular and renal diseases.
Purpose of the Study:
- To investigate the effect of lipoprotein (a) on mitogen-activated protein kinase (MAPK) signaling in human mesangial cells.
- To elucidate the specific signaling pathways, including protein kinase C (PKC) and protein kinase A (PKA), involved in Lp(a)-induced MAPK activation.
Main Methods:
- Human mesangial cells were treated with Lp(a).
- Protein kinase C (PKC) was depleted using phorbol 12-O-myristate 13-acetate.
- Adenylyl cyclase stimulators (forskolin) and a cAMP analog (dibutyryl-cAMP) were used to modulate PKA activity.
- MAPK phosphorylation and activity were measured.
Main Results:
- Lipoprotein (a) significantly increased MAPK phosphorylation and activity in human mesangial cells.
- The Lp(a)-induced MAPK activation was completely inhibited by PKC depletion.
- Forskolin and dibutyryl-cAMP reduced the effect of Lp(a) on MAPK phosphorylation and activation, indicating PKA's counteracting role.
Conclusions:
- Lipoprotein (a) stimulates the MAPK cascade through protein kinase C activation in human mesangial cells.
- Activation of protein kinase A counteracts Lp(a)-induced MAPK activation.
- These findings provide insights into the molecular mechanisms underlying Lp(a)-associated renal pathology.