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Role of cyclic AMP in idiopathic nephrotic syndrome: a pathway involving a decrease in glomerular cell heparan
B Birmelé1, A De Agostini, E P Girardin
1Départment of Pediatrics, University Hospital of Geneva, Switzerland.
Insights
Idiopathic nephrotic syndrome involves a plasma factor that decreases heparan sulfate (HS) in kidney cells. This study reveals that cyclic adenosine monophosphate (cAMP) mediates this HS reduction, offering new insights into disease mechanisms.
Area of Science:
- Nephrology
- Cellular Biology
- Biochemistry
Background:
- Idiopathic nephrotic syndrome (INS) is characterized by a circulating plasma factor that reduces heparan sulfate (HS) in the glomerular basement membrane.
- Previous in vitro studies show that patient plasma decreases glomerular cell HS.
Purpose of the Study:
- To investigate the role of cyclic adenosine monophosphate (cAMP) in the interaction between the INS plasma factor and mesangial cell HS.
- To determine if modulation of cAMP levels affects mesangial cell HS.
Main Methods:
- Incubation of mesangial cells with plasma from INS patients and control plasma.
- Measurement of cellular cAMP levels.
- Metabolic labeling to determine mesangial cell HS levels after modifying cAMP with forskolin, IBMX, or dideoxyadenosine (ddAdo).
- Assessment of the effect of ddAdo preincubation on plasma-induced HS reduction.
Main Results:
- Plasma from INS patients significantly increased mesangial cell cAMP levels compared to control plasma (+77%, P = 0.01).
- Agents that increased cAMP (forskolin, IBMX) decreased HS levels, while an agent that decreased cAMP (ddAdo) increased HS levels.
- Plasma from INS patients reduced glomerular cell HS (-34 +/- 8%, P < 0.05), an effect abolished by ddAdo preincubation.
Conclusions:
- In mesangial cells, plasma from INS patients elevates cAMP levels.
- cAMP mediates the decrease in HS levels induced by the plasma factor.
- Preventing cAMP increase inhibits the detrimental effect of the plasma factor on mesangial cell HS, suggesting cAMP's instrumental role in INS pathophysiology.
Abstract:
The physiopathological mechanisms of idiopathic nephrotic syndrome involve a circulating plasma factor and a decrease in HS in the glomerular basement membrane. Previous studies have demonstrated that plasma from patients with INS decreases glomerular cell HS in vitro. We examined the involvement of cyclic adenosine monophosphate (cAMP) in this interaction. We studied the effect of plasma from patients with INS on mesangial cell cAMP. We also determined mesangial cell HS when cAMP levels were modified using a cationic membrane after metabolic labeling. Cellular cAMP levels increased significantly when mesangial cells were incubated with plasma from patients with INS in comparison with control plasma (+77%, P = 0.01). Forskolin and IBMX, which increased cellular cAMP, decreased HS levels (-21 +/- 9% and -15 +/- 6% respectively, P < 0.05 for both), whereas dideoxyadenosine, which decreased cellular cAMP, increased HS levels (+24 +/- 7%, P < 0.05). Plasma from patients with INS decreased glomerular cell HS in comparison with control plasma (-34 +/- 8%, P < 0,05). This effect was abolished when cells were preincubated with ddAdo to prevent an increase in cAMP levels. We conclude that in mesangial cells, plasma from patients with INS increases cAMP levels, and that cAMP mediates a decrease in HS levels. Moreover, the action of plasma from patients on HS was inhibited when an increase in cAMP was prevented. cAMP may therefore be instrumental in the negative effect of the plasma factor on mesangial cell HS.