Mechanism of FK 506/520 action on rat renal proximal tubular Na+, K+-ATPase activity.
BACKGROUND
The neurotransmitter in renal sympathetic nerves, norepinephrine (NE), regulates the activity of proximal tubule (PT) Na+,K+-ATPase in a bidirectional manner via stimulation of alpha- and beta-adrenoceptors. The stimulatory alpha-adrenergic pathway is mediated by calcineurin, the target molecule for FK 506 and related compounds. We examined whether the FK 506 analogue FK 520, by interrupting the calcineurin-mediated alpha-adrenergic signaling pathway, enhance the inhibitory beta-adrenergic effect of NE on PT Na+,K+-ATPase activity.


METHODS
The effects of three days of treatment with FK 520 were examined on rat renal PT Na+,K+-ATPase activity, measured as ouabain-sensitive ATP hydrolysis in single, microdissected PT segments. Renal function studies, including glomerular filtration rate (GFR) and urinary excretion of N-acetyl-3-D-glucoseaminidase (NAG), were examined using conventional clearance techniques after three days of treatment with FK 506.


RESULTS
FK 520 treatment induced a pronounced and dose-dependent decrease in PT Na+,K+-ATPase activity. This effect was completely reversed by the competitive FK 520 antagonist, L 685 818, indicating that the effect was dependent on inhibition of calcineurin. To test whether the FK 520-induced decrease in Na+, K+-ATPase activity was mediated by enhanced beta-adrenoceptor signaling, the FK 520 effect was examined in rats pretreated with a beta-adrenoceptor antagonist (propranolol) or rats subjected to renal denervation. Both of these procedures prevented the FK 520-induced decrease in Na+,K+-ATPase activity. Thus, during FK 520 treatment, renal sympathetic nerves mediate an inhibitory effect on PT Na+,K+-ATPase activity via beta-adrenoceptors. Propranolol pretreatment also prevented FK 506-induced decreases in GFR and urinary excretion of NAG, an index of PT dysfunction.


CONCLUSIONS
The results support the hypothesis that the net effect of the neurotransmitter NE on Na+,K+-ATPase activity is dependent on the balance between the alpha- and beta-adrenergic signaling pathways and suggest that agents that interfere with these pathways may, by altering the activity of tubular Na+,K+-ATPase, also alter the function of the renal tubular epithelial cell.
Holtbäck
U
U
Department of Woman and Child Health, Karolinska Institute, Stockholm, Sweden. ullah@child.ks.se
Eklöf
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AC
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000633:toxicity*; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology* / Q000294:innervation; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D010109:Oxymetazoline / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000633:toxicity*
D007166:Immunosuppressive Agents; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D010109:Oxymetazoline; D011433:Propranolol; C058028:immunomycin; D019703:Calcineurin; D000254:Sodium-Potassium-Exchanging ATPase; D016559:Tacrolimus; D009638:Norepinephrine