Role of cyclic AMP in idiopathic nephrotic syndrome: a pathway involving a decrease in glomerular cell heparan sulfates?
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.
Birmelé
B
B
Départment of Pediatrics, University Hospital of Geneva, Switzerland.
De Agostini
A
A
Girardin
E P
EP
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000328:Adult; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005576:Colforsin / Q000494:pharmacology; D003404:Creatinine / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D016048:Dideoxyadenosine / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000378:metabolism*; D006497:Heparan Sulfate / Q000096:biosynthesis*; D006801:Humans; D009404:Nephrotic Syndrome / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010949:Plasma / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D014556:Urine / Q000502:physiology
D015056:1-Methyl-3-isobutylxanthine; D000963:Antimetabolites; D005576:Colforsin; D003404:Creatinine; D000242:Cyclic AMP; D016048:Dideoxyadenosine; D006497:Heparan Sulfate; D010726:Phosphodiesterase Inhibitors