Mechanisms through which high glucose concentration raises [Ca2+]i in renal proximal tubular cells.
BACKGROUND
The basal levels of cytosolic calcium ([Ca2+]i) of renal proximal tubular cells of rats with streptozotocin-induced diabetes are elevated. It is possible that this phenomenon is mediated by the hyperglycemia, which may cause both increased calcium influx into and/or decreased calcium efflux out of these cells.


METHODS
We examined whether high glucose concentration in vitro causes acute rise in [Ca2+]i of freshly isolated renal proximal tubular cells and explored the pathways that are involved in such an event.


RESULTS
There were dose and time dependent increments in [Ca2+]i of renal proximal tubular cells exposed to high concentrations of glucose. A similar effect was observed with equimolar concentrations of mannitol or choline chloride but not urea. A substantial part of the rise in [Ca2+]i was inhibited when the media contained verapamil, nifedipine, amlodipine or ryanodine and when the cells were placed in a calcium free media. Inhibitors of G protein(s) (GDPbetaS or pertussis toxin), inhibitors of cAMP-protein kinase A pathway (RpcAMP or H-89), inhibitors of protein kinase C (staurosporine or calphostin) and inhibitor of Na+-H+ exchanger (HOE 694) blocked the rise in a dose dependent manner. High glucose concentration also caused a decrease in ATP content of these cells and a reduction in the Vmax of their Ca2+ATPase.


CONCLUSIONS
The results are consistent with the formulation that the osmotic activity (cell shrinkage) of the high glucose concentration may activate a stretch receptor with subsequent stimulation of various cellular pathways including G protein(s), cAMP-protein kinase A and phospholipase C systems and calcium channels. Activation of these cellular pathways permits both calcium influx into renal tubular cells and mobilization of calcium from their intracellular stores. Further, a decrease in calcium efflux secondary to the reduction in the Vmax of Ca2+ ATPase may occur. It is possible that the rise in [Ca2+]i is critical for the stimulation of the events that lead to restoration of cell volume to normal.
Symonian
M
M
Department of Medicine, University of Southern California School of Medicine, Los Angeles, USA.
Smogorzewski
M
M
Marcinkowski
W
W
Krol
E
E
Massry
S G
SG
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D007700:Kinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
D002121:Calcium Channel Blockers; D000255:Adenosine Triphosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D000252:Calcium-Transporting ATPases; D005947:Glucose; D002118:Calcium